All posts by Glenda Bilder

About Glenda Bilder

PhD, University of Pennsylvania Postdoctoral studies, Roche Institute of Molecular Biology, Merck Sharp & Dohme Research Labs Preclinical Drug Discovery, Rhone-Poulenc Rorer (Sanofi-Aventis) Adjunct, Gwynedd Mercy University

Multiple Ways to Prevent Dementia

Individual controls aging, , , , ,

Introduction

Major cognitive loss, generally labeled dementia, increases with age.  Similarly, the fear and anxiety of attaining this state also increases as one ages.  Fortunately, about 40% of dementias are preventable.  The most recent scientific literature identifies 12 modifiable risk factors convincingly associated with the development of cognitive loss.  However, these factors require individual responsibility throughout the life span but undoubtedly are worth the effort as ways to prevent dementia.  These modifiable risk factors are discussed in this blog.

To begin with, there are now many types of dementias.  Thus, effort is underway to group them into a) severe neurological disorders and b) mild neurological disorders.  This has the intended goals of removing the negative connotation of dementia of which the most well known is Alzheimer’s Disease and additionally achieving a more specific diagnosis with tailored treatment for each patient.  Further, a diagnosis of mild neurological disorder may encourage lifestyle choices favorable to prevent progression to severe neurological disorder.

Modifiable Risk Factors:  relative order of highest to lowest risk

Hearing Impairment                               Smoking

Depression                                               Low Social Contact

Traumatic Brain Injury                           Diabetes

Less Education                                         Physical Inactivity

Hypertension                                             Excessive Alcohol Consumption                                

Obesity (BMI>30)                                     Air Pollution

Ways to Prevent Dementia – comments on modifiable risk factors

1.  Hearing Impairment

Hearing loss should be taken seriously as even subclinical loss is related to an increased risk of dementia.  Results of a 25 year study showed that those using hearing aids avoided cognitive decline, possibly because untreated hearing impairment reduces brain stimulation facilitating cognitive decline (see blog 16 Age-related hearing loss inadvertently printed with blog 17).  Therefore, one of the ways to prevent dementia is to correct hearing impairment.

2.  Depression

This condition is associated with an increased risk of dementia.  However, the causal factors are poorly defined and it may, in fact, be an early stage of cognitive decline, rather than depression per se.  Also whether antidepressant drug use is of benefit in preventing dementia has not been established.  Thus, one of the ways to prevent dementia is to evaluate the root cause of depression and with expert help, seek ways to lessen.

3.  Traumatic Brain Injury

Severe traumatic brain injury such as skull fracture, bleeds, edema, falls are highly associated with the development of dementia within several years of injury.  Risk is related to the severity and number of brain injuries. Therefore, ways to prevent dementia are to avoid high impact sports, improve muscle strength to evade falls and treat cardiovascular disease.

4.  Less Education

Because from birth to about twenty years of age, brain growth (new neurons, multiple connections) is optimal, better education during this period yields better protection against cognitive loss in later years.  For older individuals, there are a number of studies supporting a “use it or lose it” approach to cognitive maintenance (see Blog 6 positive neuroplasticity).  This encompasses, for example, such activities as reading, speaking a second language, physical activity, travel and retiring as late as possible.  Computerized training programs have yet to show a significant improvement impact.

5.  Hypertension

Elevated systolic blood pressure (>140 mm Hg) midlife (~ 55 years of age) elevates the risk for dementia.  If hypertension continues into later years, cognitive loss is further increased.  Numerous studies (randomized clinical trials, observational studies) indicate that aggressive lowering of blood pressure (target 120 mm Hg), regardless of the drug class, lowers the risk of dementia.  This is the basis for the American Medical Association’s new hypertension guidelines to lower systolic blood pressure below 130 mm Hg in midlife, regardless of the absence of other risk factors. Thus, one of the ways to prevent dementia is to adhere to the AMA guidelines.

6.  Obesity

A body mass index (BMI) greater than 30 is highly associated with dementia.  This was concluded from 19 longitudinal studies of over five hundred thousand individuals followed for 42 years.  There appears to be a benefit on cognitive function with weight loss in individuals with BMI >25 but the evidence needs additional validation. Thus, it is best to maintain a moderate weight to prevent dementia.

7.  Smoking

Smokers have increased mortality compared to non smokers so that defining the risk for dementia is challenging and considered biased.  However, where there is acceptable data, smoking cessation is beneficial not only on general health but also on reducing the risk of dementia long term.  Therefore, one of the ways to prevent dementia is to stop smoking or better yet, never start.

8.  Low Social Contact

Systemic and meta-analyses of studies world-wide with long term follow-up (>10 years) support factors such as marital status, associations with family and friends, community group activities and paid work as reducing this risk factor.  The effect of this risk factor appears independent of physical health and other lifestyle choices.  Intervention with discussion groups may be helpful but needs further evaluation.

9.  Diabetes

Type II Diabetes carries a risk of dementia related to the duration and severity of the disease.  Unfortunately, it is unknown, at present, which antidiabetic drug is best to prevent cognitive decline. Thus, one of the ways to prevent dementia is to control diabetes with appropriate lifestyle choices and/or medication.

10.  Physical Inactivity

In summation of multiple clinical trials (as in meta-analyses), moderate -vigorous aerobic activity (45-60 minutes for multiple days/week) decreased risk of dementia in cognitively stable individuals and improved cognition in those with mild cognitive impairment.  Also see Blogs 2-5 on exercise.

11.  Excessive Alcohol Intake

It is well established that long term heavy alcohol consumption directly damages the brain and not surprisingly contributes to dementia.  On the other hand, light to moderate drinking lessens dementia risk compared to no drinking (generally long term abstinence).  Moderate drinking is defined as no more than 21 units (one unit equivalent to10 ml or 8 grams pure alcohol/week).  However, debate continues around this as some studies show this cut-off level is too high and should be reduced by as much as 40%. Thus, one of the ways to prevent dementia is to keep alcohol consumption at a low moderate limit.

12.  Air Pollution

This risk factor relies heavily on results of animal studies.  Particulate air pollutants chemically alter the brain with vascular damage, and negative changes in amyloid and tau protein processes.  These changes lead to neurodegeneration.   One review of 13 studies assessing 1-15 years exposure to pollutants found that particulate matter, nitrogen dioxide and carbon monoxide played a significant role in promoting cognitive loss. Although challenging, one of the ways to prevent dementia is to avoid areas of known polluted air.

Ways to Prevent Dementia – Role of Diet

Readers may ask whether diet plays a role in prevention of dementia.  Scientists agree that it is difficult to accurately quantify individual diets.  Nevertheless, epidemiological (observational) studies strongly support the long term adherence to the Mediterranean and the DASH diets (diet high in plant products, nuts, legumes, olive oil and low in saturated fats, meats, salt (see blogs 10 and 11) as associated with reduction in all cause mortality including cardiovascular disease, cancers and Alzheimer’s Disease. 

Although clinical trial results disagree, it is concluded that adherence to the Mediterranean-DASH diet significantly reduces hypertension, diabetes and enhances weight loss.  Thus, it influences three of the above risk factors.  Until the Mediterranean-DASH diet becomes an independent preventive factor in cognitive loss, its influence on defined risk factors for dementia remains important.

Possible Mechanisms

The above risk factors harm the structure and function of the brain.  Structural changes of inflammation, aberrant protein deposits e.g. amyloid/tau proteins, and/or vascular damage occur with untreated diabetes, hypertension, traumatic brain injury, smoking, excessive alcohol consumption, air pollution, obesity, physical inactivity and depression.  Negative functional brain changes such as loss of or lack of maintenance of cognitive reserve are aggravated by poor childhood education, hearing impairment, low social contact as well as depression, physical inactivity and excessive alcohol intake.

Summary – Ways to Prevent Dementia

The risk factors presented in this blog are fortunately modifiable.  This means the responsibility to negate or moderate them falls on the individual.  This supports a view expressed repeated in these blogs – the individual is responsible in large part for his/her own aging.  Genetics gives one the basic components (organ systems, enzymatic processes, interconnections) but it is up to the individual to maintain them with lifestyle choices that optimize them or seek to avoid negative changes. 

If you want to know more about dementia, check out Drug Use In The Older Adult written by myself and Patricia Brown-O’Hara.

References (https://pubmed.ncbi.nlm.nih.gov/)

1.  Livingston G, Huntley J, Sommerlad A, Ames D, Ballard C, Banerjee S. et al., Dementia prevention, intervention, and care: 2020 report of the Lancet Commission. Lancet 2020; 396: 413–46. https://doi.org/10.1016/ S0140-6736(20)30367-6

2.  Northey JM, Cherbuin N, Pumpa KL, Smee DJ, Ratray B.Exercise interventions for cognitive function in adults older than 50: a systematic review with meta-analysis Br J Sports Med . 2018 Feb;52(3):154-160.  doi: 10.1136/bjsports-2016-096587. 

3.  Orgeta V, Mukadam N, Sommerlad A, Livingston G.The Lancet Commission on Dementia Prevention, Intervention, and Care: a call for action. Ir J Psychol Med. 2019 Jun;36(2):85-88. doi: 10.1017/ipm.2018.4.

4.  Jones A, Ali MU, Kenny M, Mayhew A, Mokashi V, He H et al.  Potentially Modifiable Risk Factors for Dementia and Mild Cognitive Impairment: An Umbrella Review and Meta-Analysis. Dement Geriatr Cogn Disord. 2024;53(2):91-106. doi: 10.1159/000536643

5. Rosenau C, Kohler S, Soons LM, Anstey KJ, Brayne C, Brodaty H et al., Umbrella review and Delphi study on modifiable factors for dementia risk reduction.  Alzheimer’s Dement. 2024;20:2223–2239.

6.  Abbasi J.  What to know about the New Blood Pressure Guidelines.  JAMA published online Oct 31, 2025.  doi: 10.1001/jama2025.17664

Can Blueberry Consumption Retard Aging?

Individual controls aging, ,

Introduction 

Scientists are keenly interested in the potential age and disease-preventive benefits of blueberries.  Additionally, the desire for “natural” medications to diminish risk factors of disease is popular among older adults, especially those with hypertension, diabetes and fear of mental decline.  Furthermore, the marketing hype promotes blueberry consumption as a reasonable answer to these concerns and a way to retard aging.

Interestingly, blueberries are a plausible “anti-aging” candidate.  The thought is that perhaps blueberries can retard aging. That is because these berries contain many compounds with antioxidative capability.  A prominent, although contested, theory of aging states that unabated oxidative activity drives the aging process (1).  Oxidative activity avidly damages proteins and DNA, eventually diminishing essential functions.  Hence, increasing antioxidative activity in the body with consumption of food loaded with this potential should block oxidation and retard aging. 

But can blueberry consumption provide sufficient amounts of the right kind of antioxidants to retard aging?  Over 40 clinical trials have to date tested this hypothesis.  The results as to whether blueberries can retard aging are plentiful, cautiously positive but definitely preliminary. All of this is discussed in this blog.

Inside the Blueberry

The ripe blueberry contains a selection of compounds, termed polyphenols.  The polyphenols fall into two classes: the flavonoids and the non flavonoids.  The chief contributors to antioxidant activity are the anthocyanin flavonoids.  They make up approximately 60% of the polyphenols (2).  In fact, they are the red and purple pigments in these berries.  They are the ones of most interest to researchers.

Compared to select fruits e.g. apples, raspberries, nectarines, red and black plums, grapes, strawberries, the amount of anthocyanins in blueberries (mg/3.5 oz flesh) is approximately 4-40 times higher.  Some fruits such as bananas, melons, yellow plums, oranges, kiwi contain no anthocyanins (3).

In addition to polyphenols, blueberries contain fiber, sugars, vitamin C and protein, none of which compare in concentration to the anthocyanins (4).

Exactly how much of the anthocyanins get absorbed is complex and poorly understood.  Generally, anthocyanins that are absorbed are rapidly broken down and excreted.  However, many breakdown products (metabolites) persist in tissues.  These metabolites are abundant in the large intestine due to activity of the resident bacteria (5)

Observational  Study Results

There are a number of observational studies, some fairly large, that have shown a statistical correlation between increased consumption of anthocyanins and reduced risk of cardiovascular disease, diabetes and neurological issues specifically related to Parkinson’s disease (reviewed in 3).  Although observational studies provide inspiring information for continuing investigations, they lack the scientific rigor of randomized clinical trials.

Clinical Trial Results 

Thus far, the goal of randomized clinical trials is the determination of the effect of blueberry consumption on human health in three areas:  a) reduction of risk factors for cardiovascular disease, b) increased insulin sensitivity in diabetes and c) prevention of cognitive decline.

a) Blueberries and Cardiovascular Disease

Trial results show that blueberry consumption (8 wks, freeze-dried powder or berries) lowers blood pressure (about 5%) both systolic and diastolic pressure, in post menopausal women with low grade hypertension (6) and in obese males with metabolic syndrome, a condition of abnormal lipid levels and uncontrolled blood sugar (7).   Additionally, twelve weeks of daily blueberry powder consumption lowered systolic pressure in healthy older adults (4).   In contrast, a 6 week consumption of blueberry powder in obese diabetic participants did not change blood pressure (8).  Several trials reported improvement in vascular function (increased blood flow, reduced arterial stiffness) with either freeze-dried powder or berries (4,8-11).  Consumption of blueberry equivalents of ~1.6-3 cups of berries acutely improved blood flow (dose-related manner),1-6 hours post consumption (12).

b) Blueberries and Insulin Sensitivity 

As reviewed by Stull (2016) (13), four clinical trials reported consumption of blueberries improved insulin sensitivity in patients with Type 2 Diabetes.  However, three other studies found no effect.  Apparently, differing methodologies contributed to these opposite results (13).  A 6 month trial of blueberry powder (equivalent to 1 cup blueberries) did not improve insulin sensitivity in patients with metabolic syndrome (14).  However, the addition of blueberries (one cup equivalent) after a high fat/high sugar meal, reduced the 3 hour spike in glucose and insulin and moderated the level of harmful lipids (15).  This blueberry-dependent effect is considered beneficial since a spike in sugar/lipids after a meal is the most harmful aspect of the metabolic syndrome.

c) Blueberries and Prevention of Cognitive Decline

In middle-aged overweight adults with memory complaints, 12 week of powdered blueberry (0.5 cup equivalent) improved scores on some memory and executive tests (word retrieval, memory interference, memory encoding) (16).   In a similar study with healthy older adults (65-80),  blueberry powder equivalent to 70 wild blueberries/day for 12 weeks improved word recall (4).  Twelve older adults consuming concentrated blueberry juice for 12 weeks exhibited increased brain perfusion while completing cognitive tasks compared to controls (17).

Results of a 6 month study of daily consumption of wild blueberry powder improved information reaction time assessed both with a test on the computer and electrophysiologically in those with memory complaints, 75-80 yrs of age (18).  In opposition, no effect was observed in those 60-75 years of age. Curiously, the study explanation for the difference is that memory loss in these individuals was disease-dependent and not a consequence of aging as in the older group (18).  A similarly puzzling finding occurred with 6 months supplementation with 3 different doses of blueberries (500 mg powder, 1000 mg powder and 100 mg purified extract).   In this study, several cognitive test results increased at 3 months in older adults taking the 100 mg purified extract dose.  However, cognitive response at 6 months in those consuming blueberries was no better than placebo, regardless of the dose (19). 

Assessment of Clinical Trial Results – Considerations 

It is important to review several caveats regarding the above clinical trial results with blueberries. 

First, most of these trials were funded fully or in part by blueberry associations e.g. Wild Blueberry Association of North America; US Highbush Blueberry Council.  In some cases, blueberry associations acted in  collaboration.  Such relations create a clear bias. 

Second, the trials are small enrolling 25-100 participants divided into those consuming blueberries and the controls.  On average, small trials show positive effects.  Therefore, small studies always require larger ones for confirmation.

Third, the duration of these trials is short, 6 weeks to 6 months.  A longer trial is always preferable in cases where the treatment is intended to be a life-long remedy.  Additionally, age changes are dynamic.  Evaluation of a small window gives little indication of a long term effect in a changing body.  Hence, determination of long term efficacy is essential.

Fourth, the participants in these trials consumed freeze-dried powders (17.5 -180 g/day) prepared from blueberries, with poorly defined equivalent to whole berries.  One study reported 50 g freeze-dried powder as equivalent to 2.3 cups blueberries (7) but another study stated 150 g freeze dried berries as equivalent to 1 cup of blueberries (11).  This is a relevant issue because the older adult needs to know how many berries to consume to experience the purported benefit.  Unless a blueberry powder is available as a supplement (and there are issues with supplements, see (Vitamin-mineral supplements: Are they beneficial?) and related blogs (e.g. Blog 30), whole blueberry consumption may contribute important nutrients but add nothing to retard aging.

Key Issue with Blueberries

Issue – Inter-individual Variability.  While the above caveats are correctable, the issue of inter-individual variability remains a large black box.  One of the most important clinical trials on blueberry and blueberry powder consumption revealed a huge inter-individual variability on response to vascular and cognitive changes (20).  Specifically, the results were between “31–71% of participants showing improved responses (up to +11 to +525%) and 29–66% of participants showing worsened responses (up to −12 to −141%) for the vascular and cognitive endpoints”(20).  This is related to the unique metabolic capabilities of each person and the diversity of the intestinal bacteria (20).  Absent an understanding here, application of clinical trial results to the general population of older adults is currently impossible.

Summary Points – can blueberries retard aging

1.  The data supporting an anti-aging effect of blueberry consumption are preliminary and inconclusive.

2.  Future studies need to focus on the metabolism of blueberry components before generating large long term trials testing effects in the older adult.

3.  Blueberries provide vitamin C and fiber and are a good addition to a varied healthy diet;  the data at present does not support an anti-aging effect with blueberry consumption.

Select References (https://pubmed.ncbi.nlm.nih.gov/)

Full list on request

1.  Harman D. Aging: a theory based on free radical and radiation chemistry. J Gerontol . 1956 Jul;11(3):298-300.  doi: 10.1093/geronj/11.3.298.

3. Kalt W., Cassidy A., Howard L.R., Krikorian R., Stull A.J., Tremblay F., Zamora-Ros R. Recent Research on the Health Benefits of Blueberries and Their Anthocyanins. Adv. Nutr. 2020;11:224–236. doi: 10.1093/advances/nmz065

13.  Stull AJ.  Blueberries’ Impact on Insulin Resistance and Glucose Intolerance..Antioxidants (Basel). 2016 Nov 29;5(4):44. doi: 10.3390/antiox504004419.

20. Wang Y, Haskell-Ramsay C, Gallegos JL, Lodge JK Inter-Individual Responses to a Blueberry Intervention across Multiple Endpoints. .Nutrients. 2024 Mar 20;16(6):895. doi: 10.3390/nu16060895

Advantages of Maximal Strength Training

Individual controls aging, , ,

Introduction 

This blog will discuss the nature and advantages of maximal strength training in its role of significantly improving physical function and fall prevention.  Thus, knowledge and engagement in maximal strength training is of considerable health value.

As of 2022, only 16.8% of adults, 65-74 years of age, in the USA followed the federal guidelines for aerobic and resistance exercises recommended for health maintenance (1).  Percentage participation declined further with advancing age (12.3% of 75-84 years of age and 6.2% of 85 years and older) (1).  This is indeed a disappointing record considering the plethora of benefits produced by engagement in aerobic and resistance exercises e.g. secure balance, physical endurance, assured mobility and overall continued independence  (see earlier blogs; Insight 2, Insight 3, Blog 4. Blog 5). 

Federal guideline recommend “a minimum of 150 minutes of moderate intensity or 75 minutes of vigorous aerobic activity a week and at least 2 days of activities that strengthen muscles (https://www.cdc.gov/physical-activity-basics/guidelines/older-adults.html).  Although these guidelines guarantee mobility and independence, recently reviewed data indicate that there is a difference in the results obtained with conventional strength training and maximal strength training. 

Specifically, maximal strength training provides the type of strength improvements especially needed by the older adult to prevent falls, rise with ease from a chair and climb stairs (2).  

Prevention/maintenance 

Fall prevention is imperative for the older individual because the consequences of a fall lead to a vicious downward spiral that may culminate in death.  A fall may cause muscle tears and bone fractures that require extensive rehabilitation.  In the case of hip fractures and subsequent replacement, extended hospitalization often leads to exposure to deadly pathogens (3).  Furthermore, anxiety called “fear of falling” occurs after a fall (4).  Fear of falling prompts the faller to approach mobility with caution.  This results in a change in posture and stride that rather than preventing a fall, provides the conditions for another fall (5).  Therefore, all means to prevent a fall should be of the greatest interest to the older adult.  Similarly, maintenance of mobility (chair rise, stair climb) is similarly important as reduced mobility leads to reduced independence. 

Strength Training – Maximal verses Conventional 

Maximal strength training requires that the weight of one maximal repetition (1RM) be initially determined.  1RM is the maximal weight that can be lifted once by an individual.  This varies from individual to individual. It would be low for someone with frailty and considerably higher for a physically active adult.  However, once 1RM is determined, exercises commence at least 85-90% of the 1RM (considered heavy-very heavy training) with several sets of 4 repetitions and 3-4 minutes rest between sets (2).  As muscle strength increases, the percent of 1RM increases until the initial 1RM eventually increases. 

Additionally, in maximal strength training, the concentric contraction phase (muscle shortens as the muscle contracts) of the exercise is performed as rapidly as possible. The eccentric contraction (muscle lengthens as it contracts) is performed at a slower rate.  Both upper and lower body muscles benefit from this routine.  However, the  human studies discussed here primarily used leg press, squats, or knee extension.

In contrast, conventional strength training commences at 70-75% of 1RM, generally starting at an even much lower level.  However, the number of repetitions is high, mainly 12 per sets of 2-3.  Exercises are performed with slow movement for both concentric and eccentric contractions (6).  

Age Changes in Skeletal Muscles 

As one ages, skeletal muscles if not subjected to routine resistance exercises lose both mass, strength, and power.  Sadly, loss of strength and power exceed by many fold, loss of muscle mass (7).  The composition of muscles also changes with age.  Specifically, muscles are comprised of several subtypes of fast twitch fibers (Type II) and one type of slow twitch fibers (Type  I) (8).  As indicated in the name, fast twitch Type II respond rapidly for short periods of time. Slow twitch Type I respond more slowly but for longer periods of time. 

Among the fiber types there is considerable heterogeneity and diversity allowing for the variety of human activities (8).  However, although little is known about the maintenance of diversity in muscles of the older adult, it is known that both fiber number and size decrease with age. This is attributed largely to disappearance of the motor neurons that recruits fibers for unified contraction (9).  Additionally, Type II fibers are affected to the greatest extent (10).  Resistance exercises counter loss of fibers and hence restore both mass and strength depending on the type of exercise stimulus.

Advantages of Maximal Strength Training

The advantages of maximal strength training are 3-fold.  As shown in many studies, there are the expected

(1) increase in strength (approximately 68%)

(2) a near 50% increase in the rate of force development and

(3) an increase in work efficiency (less energy used to do work)  (2, 11). 

An 8 week program of  maximal strength training in the older adult (~70 yrs) confirmed these benefits. Results additionally showed a select increase in the number and size of fast twitch Type II fibers (assessed with biopsies before and after exercise).  These changes were comparable to that of young physically active (not strength training) individuals (6).  Slow twitch Type I fibers decreased after maximal strength training.  Interestingly, conventional strength training in older adults for 8 weeks produced similar fiber changes but also increased the size of Type I fibers. This potentially negated an increase in work efficiency obtained with maximal strength training (6).  Furthermore, conventional strength training did not increase the rate force development.

Impact of maximal strength training

Both the increase in rate of force development and the increase in work efficiency, specific to maximal strength training, are key to maintenance of posture and prevention of falls.  To counteract a fall, rapid muscle response by fast twitch Type II fibers is essential.  In an experiment comparing rate of muscle force activity in a trip fall (most common type of fall), older adults compared to young adults exhibit a reduced rate of muscle force development (12).  Maximal strength training unlike conventional strength training drives neuronal recruitment to engage more muscle fibers per contraction, thus greater strength (2).  This additionally contributes to an increased rate of force development and improved work efficiency that permits a faster action with less resource.   Similarly, effects of  maximal strength training are important in “force-demanding tasks such as chair rising and stair climbing” (2).

Participants

Maximal strength training is not limited to the healthy older adult.  It has been successful in improving strength and mobility in the frail older individual (13, 14) and those with stable cardiovascular disease (15).   As reviewed in Toien et al., (2025) (2), other patient categories that include women with osteoporosis or osteopenia, survivors of a stroke, those recovering from hip fracture surgery and cancer patients receiving adjuvant therapy had engaged successfully in lower limb maximal strength training.  Compared to conventional strength training, maximal strength training increased leg strength, rate of force development, walking distance and general functional performance.

Contributions of conventional strength training.  

Conventional strength training is still important for health maintenance.  However, using resistance less than 50% of 1RM produces no improvement in muscle function (16).  To achieve increased strength, resistance greater than 50% 1RM is required and muscles must be worked to exhaustion(2). 

Conclusions 

Strength training whether conventional or maximal faciiitates life-long independence.  Maximal strength training offers additional advantages of rapid muscle response with less energy input.  Such benefits are of special assistance in fall prevention, stair climbing and getting up from a chair.  Maximal strength training is worth the effort.

References

1.  Elgaddal N, Kramarow EA.  Characteristics of Older Adults Who Met Federal Physical Activity Guidelines for Americans: United States, 2022 Natl Health Stat Report . 2024 Nov 26:(215):CS355007.  doi: 10.15620/cdc/166708.

2.  Toien T, Ber OK, Modena R, Brobakken MF, Wang E.  Heavy Strength Training in Older Adults: Implications for Health, Disease and Physical Performance J Cachexia Sarcopenia Muscle . 2025 Apr 16;16(2):e13804. doi: 10.1002/jcsm.13804

3.  Barcelo M, Torres OH, Mascaro J, Casademont J, “Hip Fracture and Mortality: Study of Specific Causes of Death and Risk Factors,” Archives of Osteoporosis 16 (2021): 15.

4.  Jung D. Fear of falling in older adults: comprehensive review. Asian Nursing Research. 2008;2:214–222. doi: 10.1016/S1976-1317(09)60003-7

5.  Jefferis BJ, Iliffe S, Kendrick D, Kerse N, Trost S, Lennon LT. How are falls and fear of falling associated with objectively measured physical activity in a cohort of community-dwelling older men? BMC Geriatr . 2014 Oct 27:14:114.  doi: 10.1186/1471-2318-14-114.

6.  Wang E , Nyberg SK, Hoff J, et al., “Impact of Maximal Strength Training on Work Efficiency and Muscle Fiber Type in the Elderly: Implications for Physical Function and Fall Prevention,” Experimental Gerontology 91 (2017): 64–71

References

7.  Lindle RA, Metter EJ Lynch NA et al., Age and gender comparisons of muscle strength in 654 women and men aged 20-93 yr J Appl Physiol (1985) . 1997 Nov;83(5):1581-7.  doi: 10.1152/jappl.1997.83.5.1581.

8   Schiaffino S, Reggiani C. Fiber types in mammalian skeletal muscles..Physiol Rev. 2011 Oct;91(4):1447-531. doi: 10.1152/physrev.00031.2010.

9. Larsson L, Ansved T. Effects of ageing on the motor unit. Prog Neurobiol 45: 397–458, 1995. doi: 10.1016/0301-0082(95)98601-Z.

10.  Larsson L, Degens H, Li M, Salviati L, Lee YI, Thompson W, Kirkland JL, Sandri M.Sarcopenia: Aging-Related Loss of Muscle Mass and Function. Physiol Rev. 2019 Jan 1;99(1):427-511. doi: 10.1152/physrev.00061.2017.

11.  Heggelund, J., Fimland, M.S., Helgerud, J., Hoff, J., 2013. Maximal strength training improves work economy, rate of force development and maximal strength more than conventional strength training. Eur. J. Appl. Physiol. 113 (6), 1565–1573.

12,  M. Pijnappels, M. F. Bobbert, and J. H. van Dieen, “Control of Support Limb Muscles in Recovery After Tripping in Young and Older Subjects,” Experimental Brain Research 160 (2005): 326–333.

13.  . Fiatarone MA, O’Neill EF, Ryan ND, et al., “Exercise Training and Nutritional Supplementation for Physical Frailty in Very Elderly People,” New England Journal of Medicine 330 (1994): 1769–1775.

14 . Singh MA, Ding W, Manfredi TJ, et al., “Insulin-Like Growth Factor I in Skeletal Muscle After Weight-Lifting Exercise in Frail Elders,” American Journal of Physiology 277 (1999): E135–E143

15.  De Oliveira JL, LimaLC, Barreto RV, et al., “Cardiovascular Responses to Unilateral, Bilateral, Upper, and Lower Limbs Resistance Exercise,” International Journal of Exercise Science 16 (2023): 1154–1164.

16.  Kamiya M., Ihira H., Taniguchi Y., et al., “Low‐Intensity Resistance Training to Improve Knee Extension Strength in Community‐Dwelling Older Adults: Systematic Review and Meta‐Analysis of Randomized Controlled Studies,” Experimental Gerontology 172 (2023): 112041

What is Successful Aging?

Individual controls aging, , , ,

Introduction

Initially, scientists viewed successful aging as an oxymoron. For them, it was inconceivable that the aging process, one of deteriorative changes, could be linked in any way to success.  However, research results gathered from individuals throughout their life, now show many ways to minimize, adjust and compensate for the effects of aging and, if followed, yield many years of quality living and well being.  Hence, the revival of the query, what constitutes successful aging to achieve the best quality of life.

Successful Aging Hypotheses

While there is, at present, no scientific consensus on the exact recipe for successful aging, there are several workable hypotheses with convincing data.   The concept of successful aging was introduced 40 years ago (1).  From then to now, successful aging has identified 14 separate components.  Four areas where at least three independent sets of data agree indicate that successful aging entails:

1.  Disease/disability prevention

2.  Satisfactory physical and cognitive functioning

3.  Engagement in life – society, social relationships and fulfilling activities

4   Subjective aging – perception of aging

Other areas with lesser support but also important, propose inclusion of a) spirituality, b) self-acceptance, c) environmental mastery, d) autonomy,  e) personal growth and f) expertise in at least one area (1).

Components of Successful Aging

Rowe and Kahn (1987) (2) distinguished between usual aging and successful aging.  These scientists observed that “the effects of the aging process itself have been exaggerated, and the modifying effects of diet, exercise, personal habits, and psychosocial factors underestimated”.   Use of these factors or interventions in a positive way ameliorates much of the effects of aging.  Later, Rowe and Kahn (1997) (3) proposed that “successful aging is multidimensional, encompassing the avoidance of disease and disability, the maintenance of high physical and cognitive function, and sustained engagement in social and productive activities”.  Psychological well being or more broadly, subjective aging has become the fourth domain of successful aging (4).

1. Disease/disability prevention – Key to Successful Aging 

There is a wealth of known risk factors for many age-related diseases, such as coronary heart disease, diabetes, chronic kidney disease and some cancers.  Most can be addressed by the responsible older adults e.g. smoking cessation, dietary changes.  Some risk factors e.g. persistent high blood pressure or elevated fasting blood sugar may require specific life style adjustments or medication that prevent disease progression (5). Various forms of osteoarthritis cause common disabilities for the older adult. Physical therapy, surgical replacements and rehabilitation ameliorate these disabilities (6). 

Most age-related diseases and disabilities are managed successfully for many years.  However, disease/disability prevention is not only desired but is also possible.  It requires individual responsibility and vigilance.  Satisfactory physical and cognitive functioning assist in disease/disability prevention.  

2.  Satisfactory physical and cognitive functioning – Key to Successful Aging. 

Numerous prior blogs (insights) discuss the validated and specific interventions to maintain physical and cognitive function.  These are lifestyle choices/interventions that have been tested through clinical trials or in the case of dietary choices with findings from epidemiological studies. 

Physical activities yielding long term gains are aerobic exercises (e.g. running, walking), resistance exercises (e.g. weights), balance and stretch exercises as discussed in insight 2 Insight 3, Insight 4, Insight 5. Cognitive maintenance and associated requisite sleep are described in insight 6, Insight 7, Brain Health and Sleep (blog 31).  Diets promoting health and associated with disease prevention are reviewed in Insight 10-Mediterranean Diet.  The interventions discussed in these blogs have been rigorously evaluated with clearly beneficial outcomes.

3.  Engagement in society, social relationships and fulfilling activities – Key to Successful Aging. 

Although there are 42 different definitions of social participation, it generally refers to “a person’s involvement in activities providing interactions with others in society or the community” (7).  This engagement with family, friends, and work (volunteer, part-time, hobbies) enhances coping and compensating strategies (8) and thus, not surprisingly, is associated with better health (9).  It is reciprocal with physical activity.  Studies show that social engagement increases physical activity which increases social activity.  In contrast, isolation produces less physical activity and greater sedentary time, both of which increase health risks (10).

4.  Positive subjective aging – perception of successful aging.   

Positive subjective aging is supportive of the above three components of successful aging.  It works through psychological, behavioral and physiological pathways to prevent diseases/disabilities, optimize physical and cognitive function and encourage social engagement (4). 

Subjective aging can be positive or negative.  The former, as stated above, links strongly with successful aging (4).  It basically encompasses one’s personal view of aging.  Generally, positive subjective aging considers oneself as physically and cognitively younger than one’s chronological age. 

Positive Subjective Aging

Positive subjective aging yields better health (4) and lower mortality (11).  Additionally, positive subjective aging engenders adaptation, positive outlook and greater likelihood of participation in healthy interventions, rehabilitation and exercise and an awareness of disease risk factors and what to do about them (12).  Results of longitudinal studies show that those with positive subjective aging exhibit better physical function, less frailty, increased independence, less depression/anxiety and less aging as determined by the degree of  inflammation (4).  Additionally, many studies associate positive subjective aging with better cognition (13).  Although less well studied, positive subjective aging produces an increase in social engagement and less loneliness (9).

Negative Subjective Aging

On the other hand, negative subjective aging accepts the stereotypic view of aging posited by others and accepts society’s ageism (14).  This results in negative self perceptions and associated poor health (14).  Specifically, negative subjective aging is associated with depression, anxiety, disease, disability (4) and engagement in risky behaviors of excess smoking, drinking, medicine non compliance, and unhealthy diets (14).

Subjective Aging Development

The development of subjective aging is complex and occurs throughout one’s life.  An individual’s perception of aging is influenced by many factors.  Some of these factors are age, gender, socioeconomic status, education, biologic/health related, general views of aging, life goals, living arrangements, psychological beliefs, coping mechanisms, and cognitive abilities (4).  Therefore, the goal is to understand this better so to channel it in a positive direction.

Conclusions

Scientists have uncovered some of the major components essential for successful aging.  Successful aging is achieved through prevention of disease and disability, maintenance of optimal levels of physical and cognitive function, active engagement in society and positive subjective aging.  All four domains are interconnected and reinforce each other.  None of these domains are unrealistic and all are achievable.

References (http://URL pubmed)

1.  Waddell C, Van Doorn G, Power G, Statham D. From Successful Ageing to Ageing Well: A Narrative Review. .Gerontologist. 2024 Dec 13;65(1):gnae109. doi: 10.1093/geront/gnae109.

2.  Rowe JW, Kahn RL. (1987). Human aging: Usual and suc­cessful. Science, 237(4811), 143–149. doi.org/10.1126/sci­ence.3299702.

3.  Rowe JW,  Kahn RL. (1997). Successful aging. Gerontologist, 37(4), 433–440. doi.org/10.1093/geront/37.4.433

4.  Sabatini6 S, Rupprecht F, Kaspar R, Klusmann V, Kornadt A, Nikitin J, Schönstein A, Stephan Y, Wettstein M, Wurm S, Diehl M, Wahl HW.  Successful Aging and Subjective Aging: Toward a Framework to Research a Neglected Connection. .Gerontologist. 2024 Dec 13;65(1):gnae051. doi: 10.1093/geront/gnae051.

5.  Bilder, GE, Brown-O’Hara, P.  Drug use in the older adult.  Guide to nurses, practicing clinicians and the interested older individual.  Chapters 4-7, Springer Nature Press, New York, 2025.

6.  Bandholm T, Husted RS, Troelsen A, Thorborg K.  Changing the narrative for exercise-based prehabilitation: Evidence-informed and shared decision making when discussing the need for a total knee arthroplasty with patients. Osteoarthr Cartil Open. 2025 Mar 12;7(2):100601. doi: 10.1016/j.ocarto.2025.100601.

References (continued)

7.  Levasseur M, Richard L, Gauvin L, Raymond E.  Inventory and analysis of definitions of social participation found in the aging literature: proposed taxonomy of social activities. .Soc Sci Med. 2010 Dec;71(12):2141-9. doi: 10.1016/j.socscimed.2010.09.041.

8.  Reker, G. (2009). A brief manual of the Successful Aging Scale (SAS).

9.  Douglas H, Georgiou A, Westbrook J. 2017. Social participation as an indicator of successful aging: an overview of concepts and their associations with health. Aust. Health Rev. 41:455–62.

10.  Schrempft S, Jackowska M, HamerM, SteptoeA. 2019.  Associations between social isolation,loneliness, and objective physical activity in older men and women. BMC Public Health 19:74.

11.  Westerhof GJ, Nehrkorn-Bailey AM, Tsen H-Y, Brothers A, Siebert JS, Wurm S, Wahl H-W,  Diehl M. (2023). Longitudinal effects of subjective aging on health and longevity: An updated meta-analysis. Psychology and Aging, 38(3), 147–166. doi.org/ 10.1037/pag0000737.

12.  Diehl M, Rebok GW, Roth DL, Nehrkorn-Bailey A, Rodriguez D, Tseng H-Y, Chen D. (2023). Examining the malleability of negative views of aging, self-efficacy beliefs, and behavioral intentions in middle-aged and older adults. Journals of Gerontology, Series B: Psychological Sciences and Social Sciences, 78, 2009–2020. doi.org/ 10.1093/geronb/gbad130.

13.  Fernández-Ballbé O, Martin-Moratinos M, Saiz J, Gallardo-Peralta L,  Barrón López de Roda A. (2023). The relationship between subjective aging and cognition in elderly people: A systematic review. Healthcare, 11(24), 3115. doi.org/10.3390/health­care11243115.

14.  Chang E-S, Kannoth S, Levy S., Wang S-Y, Lee J. E, Levy BR. (2020).  Global reach of ageism on older persons’ health: A system­atic review. PLoS One, 15(1), e0220857.

Modifiable Factors Making Sleep Better

Individual controls aging, ,

Introduction  

From the wealth of available sleep aids that are heavily marketed to older adults, the impression is that a good night’s sleep diminishes with age and medicinal or herbal sleep aids are essential.  The truth is that aging per se has little negative impact on sleep1.  However, there are many factors, related and unrelated to aging, that may perturb sleep and hinder one to sleep better.  This blog is about modifiable factors making sleep better. 

Sleep Complaints 

Several recent reviews on sleep in the older adult report that a high percentage (up to nearly 50%) of older adults have sleep complains relating to difficulty falling asleep and staying asleep2-4.  Significantly, delving deeper reveals that poor health and associated issues, not age per se, is the main driver of sleep complaints.  In fact, sleep problems fell to 18% when factors such as “poorer self-rated health, elevated depressive symptomatology and increasing number of physical disabilities, respiratory symptoms and nonprescription medication …. and use of prescription medication” were accounted for5.

Notably, many of these complaint-related factors are, in fact, modifiable.  Importantly, when removed or mitigated, various aspects of sleep improve such as time to fall asleep, duration of quality sleep, fewer interruptions, feeling rested the next morning.  The modifiable factors making sleep better that need evaluation and change are:

1.  Diseases/disorders not adequately treated such as cardiopulmonary diseases (conditions that affect normal breathing), gastric reflux disorder (gastric contents enters esophagus causing chest pain) and chronic pain (such as osteoarthritic pain)

2.  Prescription medications known to negatively affect sleep e.g. beta blockers (anti-hypertensives), bronchodilators (generally for chronic obstructive pulmonary disease), antidepressants (anxiety/depression)

3.  Use of sleep aids: prescription or over-the-counter (OTC)

4.  Behavioral factors: poor sleep hygiene, daytime napping, excessive use of alcohol and caffeine

5.  Life style choice:  reduced physical activity

Therefore, there is scientific evidence to support the aforementioned factors as sleep disruptors and additional evidence suggesting a way toward better sleep.

Diseases/disorders

# 1 – Related to certain diseases/disorders.  Probably the most difficult to quickly resolve are sleep issues relating to specific medical conditions.  The top three sleep disrupters are diseases affecting adequate breathing, reflux of gastric contents and conditions producing chronic pain.  Clearly, these are prominent factors that affect sleep in many way.  Specifically, a resolution comes with discussion between patient and doctor to prescribe therapies that promote better breathing, quiescent gastrointestinal tract and no pain with therapies that also promote restful sleep.  Such therapies, pharmacological and non pharmacological exist6-8. 

Prescription Medications – Modifiable Factor making sleep better

# 2 – Several prescription medications stand out as enablers of poor sleep.  Specifically, the drugs in the class of beta-blockers e.g. Lopressor® are able to reduce effects of melatonin, the natural sleep hormone, disrupting sleep9.  Also, antidepressants e.g. Prozac®, Pristiq® elevate the levels of neurotransmitters, serotonin and norepinephrine to stimulate the brain and alter sleep10.  Additionally, bronchodilators e.g. Proair® if taken too close to bedtime will produce a stimulatory effect as well11.  Importantly, drugs from other classes with difference mechanisms of action are available to lower blood pressure, relieve depression and assist with breathing to aid with sleep.  However, as with #1 modifiable factor, physician-patient discussion is essential to put these changes into effect.

Sleep Aids – Modifiable Factor making sleep better

#3a – Prescription Sleep Aids to Avoid.  The benzodiazepine class of drugs (examples: Xanax®, Valium®, Librium®) and are widely prescribed as sleep aids12.  Many reviews report only a modest effect on sleep coupled with a great potential for dependence, both physiological and psychological12.  Thus, these drugs are contraindicated in the older adult because they increase the risk of falls, daytime sedation, memory concerns and car accidents.  Hence, physician-directed slow benzodiazepine withdrawal is highly recommended for those already taking benzodiazepines13.  Another class called Z-drugs e.g. Lunesta®, Sonata®, Ambien® have similar problems as the benzodiazepines and additionally may cause complex sleep behaviors resulting in sleep walking or other unusual behavior that may cause injury (FDA.gov)   

A third class is the barbiturates e.g. Fiorina®, Pentothal®, Seconal®, although used less frequently, nevertheless, these drugs are still prescribed as sleep aids.  For the older adult, barbiturates are considered potentially inappropriate medications (PIMS).  A panel of experts with a thorough review of the literature has made this recommendation14.  This is based on evidence of eventual tolerance to sleep, physical dependence and risk of overdose.

OTC Drugs

3b. OTC drugs for sleep to avoid.  The list of OTC sleep aids is extensive.  Those marketed for this reasons include OTC drugs and OTC dietary supplements.  Among the OTC drugs are the antihistamines, diphenhydramine hydrochloride (Benedryl®, ZzzQuil®, Simply Sleep®), and doxylamine succinate (Unisom®).  OTC drug must show safety and efficacy sufficient for FDA approval.   However, for the older adult, antihistamines are considered potentially inappropriate medications14.   Antihistamines cause sedation, dry mouth, blurred vision, urinary retention, constipation, confusion, increased heart rate, heat intolerance, hallucinations.  These effects are harmful in themselves and are additive to many other medications leading to serious adverse drug reactions.  Antihistamines as sleep aids should be avoided.

3c. OTC dietary supplements to avoid. The second group of OTC sleep aids are classified as dietary supplements.  They include products such as melatonin, St. Johns Wort, valerian, L-tryptophan.  As indicated in the preceding blog (Turmeric) dietary supplements are not regulated in the same manner as OTC drugs.  Thus, dietary supplements marketed as sleep aids have not been tested clinically for safety and efficacy15.  Reports of published clinical trials on these dietary supplements used proprietary preparations or prescription drugs (as in the case of melatonin).  Thus “tested” products are products are not available OTC.  The reader can find study details on melatonin and St John’s Wort in my upcoming book coauthored with Dr. Patricia Brown-O’Hara, Drug Use in the Older Adult – A Guide for Nurses, other Practicing Clinicians and Interested Older Individuals.

Behavior – Modifiable Factor making sleep better

#4- Behavioral Changes.  Cognitive Behavioral Therapy (CBT) is the gold standard for therapy of insomnia and other diagnosed sleep disorders that exceed the level of sleep complaints.  However, aspects of CBT can be practiced effectively to enhance sleep. In the category of sleep hygiene, effective changes include:  use the bed for sleep not for work or iphone/ipad perusing, use the bed only when sleepy and if not sleepy, get up for a period of 20-30 minutes and repeat if necessary; get up at the same time each day (use an alarm clock if necessary), establish regular sleeping hours16.  Other behavioral changes are to  avoid daytime napping11, and avoid elevated consumption of alcohol17, caffeine17, smoking and large meals 2 hours before bed time.

Lifestyle

# 5 – Lifestyle Choice.  In addition to behavioral changes, lifestyle changes have become important.  One focus is on physical activity.  Results of one study in older women (360, one week assessment) showed a positive relation between moderate-vigorous physical activity plus time spent outdoors with longer sleep duration18.  A 12 month study with fewer older adults (55+ years, 36 in exercise and 30 controls) performing moderate-intensity endurance exercise (5 days/week; 60 minute sessions, aerobics, resistance, stretch and balance) exhibited reduce sleep latency, reduced number of awakenings and overall feeling of being more rested19.  A third study assessed with questionnaires concluded that moderate low-intensity exercise was a significant factor in preventing insomnia 20.   While a serious exercise program offers many health benefits (Insight 3 Insight 4), larger clinical trials are needed to rigorously support moderate-intensity exercise as effective in reducing all sleep complaints.  For more discussion, check http://sleepwellns.ca/; http://thesleepreset.com; http://lp.stellarsleep.com.

Conclusions

It is unrealistic to blame poor sleep on growing older.  Sleep complaints can be minimized or eliminated with review of the modifiable factors making sleep better. These are inadequately treated diseases/disorders, certain prescription drugs, sleep aids (prescription and OTC products), poor sleep hygiene and reduced physical activity. 

References

1.  Ohayon MM, Carskadon MA, Guilleminault C, Vitiello MV. Meta-analysis of quantitative sleep parameters from childhood to old age in healthy individuals: Developing normative sleep values across the human lifespan. Sleep. 2004;27:1255–1273.

2.  Miner B, Kryger MH. Sleep in the Aging Population. Miner B, Kryger MH.Sleep Med Clin. 2017 Mar;12(1):31-38.

3.  Stephan Y, Sutin AR, Bayard S, Terracciano A. Subjective age and sleep in middle-aged and older adults. .Psychol Health. 2017 Sep;32(9):1140-1151.

4.  Min Y, Nadpara PA, Slattum PW. The association between sleep problems, sleep medication use, and falls in community-dwelling older adults: results from the health and retirement study 2010. J Aging Res. 2016;2016:3685789.

5.  Foley DJ, Monjan AA, Brown SL et al. Sleep complaints among elderly persons: An epidemiologic study of three communities. Sleep. 1995;18:425–432

6.  Pain Haack M, Simpson N, Sethna N et al. Sleep deficiency and chronic pain: potential underlying mechanisms and clinical implications. .Neuropsychopharmacology. 2020 Jan;45(1):205-216.

7.  Shaheen NJ, Madanick RD, Alattar M et al. Gastroesophageal reflux disease as an etiology of sleep disturbance in subjects with insomnia and minimal reflux symptoms: a pilot study of prevalence and response to therapy. Dig Dis Sci. 2008 Jun;53(6):1493-9

8.  Sharafkhaneh A, Jayaraman G, Kaleekal T et al. Sleep disorders and their management in patients with COPD. Ther Adv Respir Dis. 2009 Dec;3(6):309-18

9.  Mayeda A, Mannon S, Hofstetter J et al. Effects of indirect light and propranolol on melatonin levels in normal human subjects. .Psychiatry Res. 1998 Oct 19;81(1):9-17

10. Wichniak et al., Effects of Antidepressants on Sleep Curr Psychiatry Rep. 2017 Aug 9;19(9):63.  

11.  Tatineny P, Shafi F, Gohar A, Bhat A. Sleep in the Elderly. Mo Med. 2020 Sep-Oct;117(5):490-495

More References

12.  Holbrook AM, Crowther R, Lotter A et al. Meta-analysis of benzodiazepine use in the treatment of insomnia. CMAJ 2000;162(2):225-33

13.  Pottie K, Thompson W, Davies S, et al. Deprescribing benzodiazepine receptor agonists: evidence-based clinical practice guideline. Can Fam Physician 2018; 64(5):339–351

14.  By the 2023 American Geriatrics Society Beers Criteria® Update Expert Panel. American Geriatrics Society 2023 updated AGS Beers Criteria® for potentially inappropriate medication use in older adults. J Am Geriatr Soc. 2023 Jul;71(7):2052-2081.

15.  Culpepper L, Wingertzahn MA. Over-the-Counter Agents for the Treatment of Occasional Disturbed Sleep or Transient Insomnia: A Systematic Review of Efficacy and Safety. Prim Care Companion CNS Disord. 2015 Dec 31;17(6):10.4088/PCC.15r01798.

16.  Sejbuk M, Mirończuk-Chodakowska I, Witkowska AM. Sleep Quality: A Narrative Review on Nutrition, Stimulants, and Physical Activity as Important Factors. Nutrients. 2022 May 2;14(9):1912.18.  

17.  Thakkar MM, Sharma R, Sahota P. Alcohol disrupts sleep homeostasis. .Alcohol. 2015 Jun;49(4):299-310. 18.  Gardiner C, Weakley J, Burke LM, et al. The effect of caffeine on subsequent sleep: A systematic review and meta-analysis. Sleep Med Rev. 2023 Jun;69:101764.

18.  Murray K, Godbole S, Natarajan L, et al. The relations between sleep, time of physical activity, and time outdoors among adult women. PLoS ONE. 2017;12:e0182013

19.  King AC, Pruitt LA, Woo S, et al. Effects of moderate-intensity exercise on polysomnographic and subjective sleep quality in older adults with mild to moderate sleep complaints. J Gerontol A Biol Sci Med Sci. 2008;63:997–1004.

20.  Tsunoda K, Kitano N, Kai Y et al. Prospective study of physical activity and sleep in middle-aged and older adults. Am. J. Prev. Med. 2015;48:662–673.

Turmeric Extracts: Treasure or Trouble?

Turmeric Extracts, ,

Extracts of turmeric, the root of the Curcuma longa plant is credited with many health enhancing qualities.  These are 1) reduction of pain and debilitation of osteoarthritis, 2) inhibition of cancer growth, and 3) slowing of age-related cognitive decline, to name a few.  These benefits are the reported and marketed treasures of turmeric extracts.  Many older adults self medicate with turmeric extracts because of these claims.  However, the trouble is simply that turmeric extracts are poorly bioavailable (are not absorbed and remain in the gut) and hence the chemical characteristics of turmeric extracts prevent a meaningful biological effect. 

Historically, the initial excitement claiming turmeric extracts caused a perfusion of effects (antioxidative, anti-inflammatory, anticancer) derived from assays lacking relevant controls.  This published data persists and is abundantly quoted.  Many clinical trials assessed the benefits of turmeric extracts, but trials are small and results preliminary and controversial.

This blog will discuss the pros and cons of turmeric extracts relevant to purported health benefits in joint pain and cognitive decline, conditions of interest to the older adult.

Turmeric Extracts:  Curcumin is the Biological Component of Interest

Powdered turmeric is a popular yellow spice.  It is used on its own for its distinct flavor, as a significant component of curry powder and as a yellow food coloring.  Additionally, alcohol extracts of the turmeric root have been used for centuries as an Asian herbal remedy for a variety of health problems and is currently the form studied in clinical trials for many of those same conditions. 

The “active” components in alcohol extracted turmeric roots are chemical entities identified as curcuminoids, chief of which is curcumin.  Two other curcuminoids with slightly modified chemical structures are also present but in very small amounts.  Health benefits are predominately attributed to curcumin.  Over-the-counter (OTC) turmeric extracts contain 80% or more of curcumin.  However, the curcumin content of turmeric extracts vary from supplier to supplier.  Turmeric extracts are dietary supplements. Unlike prescription drugs, the FDA does not regulate dietary supplements for efficacy and safety.  Suppliers of dietary supplements need only follow good manufacturing practices (GMP) without governmental oversight.

Curcumin:  Poorly Bioavailable and Chemically Unstable

Absorption of curcumin into the body after oral intake is extremely poor.  In fact, the absorption of curcumin is negligible and generally not even detectable in serum even after consumption of as much as12 grams/day.  This is largely due to the chemical structure of curcumin.  It is unstable in biological fluids at biological temperatures.  Adding to this is its inability to cross the intestinal wall and its breakdown in the liver.  Consequently, it never gets into body compartments to induce a meaningful effect.

The abysmal absorption of curcumin has generated extreme interest in the development of chemical/physical modifications to enhance absorption.  In a study comparing novel formulations such as curcumin associated with fats, oils, adjuvants e.g. piperine (black pepper derivative), carbohydrates e.g. gamma cyclodextrin and micelles (nanoparticles encapsulating curcumin) only the latter two improved absorption to the extent that a metabolic product of curcumin but not curcumin, itself, was detected in the serum.  With such a weak presence in serum, it is reasonable to ask how can curcumin exert biological effects?

Turmeric Extracts – Multiplicity of Health Benefits of Curcumin?

Some of the reported beneficial effects of curcumin are “anti-inflammatory, anti-HIV, antibacterial, antifungal, nematocidal (killing nematode infection), anti-parasitic, antimutagenic (blocking DNA damage), antidiabetic, antifibrinogenic (preventing blood clots), radioprotective (protecting against radiation), wound healing, lipid lowering, antispasmodic (relieving muscle cramps), antioxidant, immunomodulating (assisting the immune system), anticarcinogenic” (Nelson et al., 2017). 

However, a critical review of the in vitro assays that support this diversity of effects indicates that the chemical instability of curcumin artificially interferes with assay results such that the results are not biological but simply artefactual (not real).  In fact, curcumin is a pan-assay interference compound.  This means that it creates havoc in assays.  It does this is by disruption of cell membranes, inappropriately binding to proteins, forming aggregates (bunching up of proteins) and/or altering the fluorescence detection readout, as some examples.  These activities are unrelated to the biological objective of the assay.  Very few studies have controlled for these unwanted and interfering effects.  Thus, exactly what biological effects curcumin may possess is not clear.

Turmeric Extracts – Clinical Trial Results

Many small studies (20-200 enrolled individuals) assessed curcumin for the treatment of osteoarthritis, cancer, and cognitive decline.  Since the results of a single small study carries little weight, researchers use a statistical approach termed a meta-analysis.  This allows the data from similar clinical trials to be added together and statistically analyzed, a technique that strengthens the final conclusion.  However, inclusion of a clinical trial in a meta-analysis must meet strict criteria e.g. randomization, clear end  points, accurate verifiable measurements, specified duration and many more.  Out of hundreds of trials, usually 7-20 or so make the cut into a meta-analysis.

Likely Use of Turmeric Extracts by Older Individuals

Most older adults have some degree of joint inflammation known as osteoarthritis.  The joint inflammation produces pain, stiffness, and swelling and limits mobility.  An effective therapy is the use of the nonsteroidal antiinflammatory OTC drugs e.g. naproxen and ibuprofen.  However, some also seek herbal remedies such as turmeric extracts (curcumin) that are touted as highly effective treatments for osteoarthritis. 

1.  Do turmeric extracts reduced debilitating symptoms of osteoarthritis?

A meta-analysis of curcumin use in knee-osteoarthritis identified 8 clinical trials that met their criteria.  Two subjective assessment scores, accepted as both valid and reliable defined the severity of pain, stiffness and swelling.   The USA completed one trial and Asia and Italy the others.  Turmeric extract (curcumin ~1000 mg/day) used for 4 weeks to 4 months in 45-100 subjects reduced symptoms of knee osteoarthritis.  Adverse effects were no different than placebo or OTC antiinflammatory medications.  However, since the total number of patients was small (even when all studies were combined) and there was some quality issues with the data, these results are not considered definitive.  Furthermore, some of the trials used proprietary preparations of curcumin, not available OTC.  

Three more recent meta-analyses (2021-2022) found that turmeric extracts ameliorated symptoms of knee osteoarthritis compared to placebo and comparable to OTC anti-inflammatory drugs.  These analyses each included a greater number of clinical trials (15-16), hence combining a greater number of subjects (up to 1800 subjects total). Most trials used proprietary formulations of curcumin.  India, China, Iran and Thailand hosted the majority of studies.   However, the authors of all meta-analyses projected caution in interpretation of results due to poor quality of the data and presence of moderate bias.

Another likely use of Turmeric Extracts.

Older adults are anxious that their mental acuity may decline with age.  Hence, remedies that prevent or at least slow cognitive decline are of keen interest.  Turmeric extracts are marketed as beneficial in this respect.

2.  Do turmeric extracts reduce cognitive decline?

Results of clinical trial thus far are not convincing that consumption of turmeric extracts improves thinking ability.  There are no meta-analyses.  Eight clinical trials (2008 -2020) assessed the effect of turmeric extracts (curcumin) consumption on cognitive function in older adults.  Studies were small (27-152 subjects), lasting 4 weeks to 1 year, and most used proprietary preparations of curcumin or precisely defined the amount of extracted curcumin in each capsule.

Subjects completed a battery of mental tests that examine a range of cognitive domains.  Short term memory improved in 2 of the 8 trials. Other cognitive domains did not improve. In one trial, short term memory improved at 6 hours post dosing and at 4 weeks of daily dosing in prediabetic subjects.  In another study, 16 weeks of daily dosing in overweight/obese males (not females) increased short term memory.  Immediate recall tests (e.g. recalling a list of 15 words after specified time periods or performing serial subtraction of, for example, 7 from 100) served to assess short term memory.  How results of these memory test translate into enhanced daily thinking in general is unclear. 

Are Turmeric Extracts Safe?

The FDA considers the turmeric spice a generally recognized as safe (GRAS) product (FDA notice 460) when added to food (for flavor, flavor enhancement) at 20 mg/serving.   Companies marketing curcuminoids may receive a GRAS label if they submit extensive data to the FDA on chemistry, specifications, and toxicology in animals and humans.  One example is GRAS notice 822 from Laurus Labs.  Laurus Lab’s curcumin received the GRAS label when used at 0.5-100 mg/100 g of food.  However, most companies do not have FDA GRAS approval for their OTC curcumin product. 

In human clinical trials, use of gram doses of turmeric extracts appear safe.  Results of clinical trials report adverse effects comparable to placebo or antiinflammatory drugs (e.g. ibuprofen).  Adverse effects generally include various types of gastrointestinal (GI) upsets.  This is not surprising since turmeric extracts are poorly absorbed (even preps modified to improve absorption) and thus these products basically remain in the GI tract until eliminated.

How to explain the small biological effects of turmeric extracts?

The active component of turmeric extracts, the curcuminoids, are incredibly chemically unstable in and out of the human body.  How then to explain the small effects reported in clinical trials.  This is possibly a result of the small number of participants in these trials that generate considerable bias and hence false results.  Alternatively, it has been proposed that the persistence of the curcuminoids in the GI tract allows interaction with the thousands of resident bacteria. These bacteria produce mediators to account for the anti-inflammatory effects in osteoarthritis and the slight immediate recall benefit. 

This is an interesting concept but given the extensive number and diversity of GI bacteria, and the variation from one individual to another, this remains a challenging hypothesis to study and prove.  For the time being, it is reasonably better to engage in a serious exercise program (insight 2) (insight 3) (insight 4) and participate in activities that enhance positive neuroplasticity of the brain (insight 6) to ameliorate symptoms of osteoarthritis and cognitive decline.

Conclusions

Review of the biology of turmeric extracts (curcumin) shows evidence of it poor bioavailability/chemical instability and inconclusive clinical trial results relevant to osteoarthritis and cognitive decline.   Clearly, it is premature to consider this herbal remedy as of value in self-medication for joint pain and memory complaints. A large randomized clinical trial (several thousand subjects) using several doses over a period of months with turmeric extract readily available OTC would provide a definite answer.

This is one of several blogs that will review some of the OTC health products.  Readers interested in a wider range of OTC drugs and dietary supplements, might check out the book: Drug Use in the Older Adult: Guide to Nurses, Other Practicing Clinicians and the Interested Older Individual authored  by myself and Dr. Patricia Brown-O’Hara, expected out this spring.  One full chapter discusses use of OTC products (drugs and dietary supplements).  Ask your local librarian to purchase it as a necessary reference.

Selected References (http//pubmed) Additional references on request

Daily JW, Yang M, Park S.  Efficacy of Turmeric Extracts and Curcumin for Alleviating the Symptoms of Joint Arthritis: A Systematic Review and Meta-Analysis of Randomized Clinical Trials J Med Food 19 (8) 2016, 717–729DOI: 10.1089/jmf.2016.3705.

Nelson KM,Dahlin JL, Bisson J, Graham J, Pauli GF, Walters MA.  The Essential Medicinal Chemistry of Curcumin Miniperspective. J. Med. Chem. 2017, 60, 1620−1637 DOI: 10.1021/acs.jmedchem.6b00975.

Prasad S, Gupta SC, Tyagi AK, Aggarwal BB: Curcumin, a component of golden spice: From bedside to bench and back. Biotechnol Adv 2014;32:1053–1064.

Rainey-Smith SR, Brown BM, Sohrabi HR, Shah T, Goozee KG, Gupta VB, Martins RN. Curcumin and cognition: a randomised, placebo-controlled, double-blind study of community-dwelling older adults. Br J Nutr. 2016 Jun;115(12):2106-13. doi: 10.1017/S0007114516001203.

Turmeric: the Spice

Risk of fractures – how important is dietary/supplemental calcium?

Dietary/supplemental calcium, Individual controls aging, , , ,

Introduction

The premise that calcium consumption makes bones stronger must be qualified by age.  It is well established that bone formation, up to 35 years of age, is the prominent activity in bone.  During this time, strong bone formation depends on adequate calcium intake and stress/strain on bone (i.e. physical activity).  Strong bones resist fractures and thereby allow for unlimited mobility and independence. 

However, in the older adult (after age 35), bone formation ceases and is replaced by remodeling, a type of repair of microdamage.  Calcium may relocate in bone but chronic accumulation of additional calcium driven by calcium consumption does not occur.  Therefore, as this blog will discuss, neither dietary nor supplemental calcium puts calcium back into bones of older adults and furthermore, neither has an effect on reducing the risk of fractures. In particular, several adverse effects are associated with use of calcium supplements.

Bone biology

The bones of our skeletal system serve many important functions.  Bones support our muscles for balance, provide form and allow mobility.  Bones protect our internal organs (lungs, heart, brain), and act as the largest reservoir for the essential mineral, calcium. 

Importance of calcium

The body requires calcium for just about every function in the body.  This includes the contraction of our muscles, nerve conduction and release of neurotransmitters, enzyme activity for metabolism, and secretion of hormones and bioactive factors, to name a few. 

Two hormones, the parathyroid hormone and calcitonin, assure that blood calcium is tightly controlled within a narrow range so that these functions are adequately maintained.  Although rare, blood calcium levels that are too high or too low produce adverse effects.  For example, chronic high levels of calcium produce kidney stones and chronic low levels of calcium produce thin weak bones.

Bone Formation in the Young Adult

The optimal time to increase bone density is during growth up to 35 years of age.  Thus, the greater the bone density at age 35, the less likely the occurrence of a fracture as one ages, even in the presence of unavoidable menopausal-driven bone calcium loss.  Assuming a normal diet with adequate calcium intake, achieving high bone density throughout one’s growth by participating in sports, work-outs, and/or physically demanding activities,  is the only way to prevent osteoporosis in later life. 

A diagnosis of osteoporosis is given when density of bone minerals i.e. calcium reaches a predetermined value (in comparison to the average bone density of a 30 year old).  This chosen low density value is significant because it indicates an elevated risk of a fracture.  Osteoporosis is managed with one of several prescription drugs that act to strengthen bones. 

Bone Loss in the Older Adult

Bone mineral density declines with age in both women and men due to key factors such as hormonal changes, loss of muscle mass and reduced level of physical activity.  However, the impact on older women is especially acute due to 1) the lower level of bone mineral density achieved early in life (smaller muscle mass and reduced participation in sports) and 2) the severe reduction of estrogen with menopause. 

Estrogen is the premier driver of bone formation.  Estrogen production largely ceases in menopause (around 50-55 years) and is slightly reduced in older males.  This change results in a significant decline in bone maintenance and remodeling leading to subsequent loss of bone minerals.  Bones become less dense and less strong with an elevated potential for fractures on minimal impact.

Benefit/risk assessment of calcium supplements and risk of fractures

The daily use of calcium supplements with or without added vitamin D is widespread among middle-aged and postmenopausal women.  This activity supported a 3.8 billion dollar industry in 2022 with a projected doubling in 2023 (https://www.futuremarketinsights.com/reports/calcium-supplements-market).

Beginning in the 1980s, with very little human data, the medical and pharmaceutical industry promoted consumption of calcium supplements for optimal bone health.  Whereas the calcium-deficient individual benefitted from calcium plus vitamin D supplements in the treatment of serious bone loss diseases (osteoporosis, osteomalacia) with its high risk of fractures, individuals without calcium deficiency and no bone disease were similarly assumed to benefit from calcium supplements that were purported to create stronger bones, and hence fewer fractures.  The data from many randomized clinical trials do not support this.

Calcium supplements do not prevent fractures

The loss of bone calcium with age prompted the use of calcium supplements with and without vitamin D to reverse this.  Sadly, this does not work.  The few studies that measured bone density during use of calcium supplements found only transient small increases in bone density that were not preserved over time (1).  In other words, there was no consistent and persistent increase in bone density.  Most importantly, the result of numerous randomized clinical trials concluded that the use of calcium supplements has no effect on the main endpoint, prevention of fractures. 

Meta-analysis

To assess the massive literature on the relation of calcium supplements to fracture risk, the meta-analysis approach selects and critiques the best (low bias) randomized clinical trials.  Among all studies relating to calcium supplements and fractures, those selected for the meta-analysis meet rigorous criteria such as randomization, placebo control, duration greater than 1 year, adults over 50 years, and specific validated endpoint e.g. evidence of a fracture.  The results of 6 meta-analyses (2-7) each analyzing 10-20 trials concluded that consumption of calcium with or without vitamin D did not change the risk for fractures (hip, vertebral, non vertebral) in community-dwelling older adults.  The one exception, noted in one study (8), calcium supplements benefit frail institutionalized older adults with osteoporosis. 

Calcium supplements exert adverse effects

1.  Cardiovascular risk

There has been a long standing concern that calcium supplements may adversely affect the heart and blood vessels.  In support of this concern are the results from a major “study assessing the association of calcium intake, source of calcium intake, and coronary artery calcification in a large, multiethnic sample of US men and women at both baseline and with repeat longitudinal estimates of incident coronary artery calcification up to 10 years” (9).  Importantly, coronary artery calcification was associated with calcium supplement intake but not with dietary calcium intake.  Coronary artery calcification is a biomarker of cardiovascular risk because calcium locates to artery plaques.  Hence, its presence may contribute to plaque formation and increase the risk for heart disease.

1a. Important clinical trials

There have been numerous clinical trials examining the relation of calcium supplements to risk of cardiovascular disease, clinically as defined by a heart attack, stroke or cardiovascular death. Using meta-analysis, it is concluded that use of calcium supplements increases the risk of cardiovascular disease (10-12).  In contrast, unlike calcium supplements, one meta-analysis reported that dietary calcium did not increase the risk of cardiovascular disease (10). 

An additional study of note because of its long duration of 20 year is a prospective cohort study (13).  This study concluded that calcium supplements do not increase the risk for cardiovascular disease. However, unlike a randomized clinical trial in which randomization and placebo controls are required to reduce bias, the prospective cohort study tracks individuals over a long period, taking measurements throughout but without randomization or controls.

2.  Kidney stones and GI issues

Although not as well investigated as adverse cardiovascular effects, gastrointestinal effects, in particular constipation is associated with intake of calcium supplements.  It is generally considered a minor issue but in fact, it is the main reason for lack of compliance in clinical trials with calcium supplements (14).

Additionally, use of calcium supplements increases urinary calcium (15) which has the potential to cause kidney stones.  Inadequate fluid intake elevates the risk of kidney stones with calcium supplements (16).

Dietary Calcium and Fractures

Meta-analysis of clinical trials show that dietary calcium intake can fluctuate significantly and still have no effect on risk of fracture.   A relevant example is the Auckland Calcium Study which followed 500 postmenopausal women (not taking hormone replacement therapy or calcium supplements) and measuring bone density numerous times over a 5 year period.  Dietary calcium ranging from 400-1500 mg/day had no effect on the number of fractures (1).  Anderson et al., 2016 cited above, reported that while calcium supplement intake is associated with coronary artery calcification, dietary calcium intake is not.  Dietary calcium also is not associated with adverse effects evident with calcium supplements (10).

RDA and Fractures

It is clear that ingesting calcium by diet or by supplements does little to fortify the bones in older adults.  So why bother about even dietary calcium consumption?  The answer is that dietary calcium is essential for a vast variety of physiological activities such as muscle contraction and nerve activity (see Importance of Calcium section).  Thus the need for a recommended daily allowance (RDA).  If the RDA is not met, then the body will “steal” calcium from the best depot, bone.

The Food and Nutrition Board sets the RDA (https://www.nationalacademies.org/fnb/food-and-nutrition-board).   For women over 50 years of age, the calcium RDA is 1200/day.  For men 51-70  years of age, it is 1000 mg/day and 1200 mg/day for men over 70 years of age.   Interestingly, calcium RDA is based on results of calcium balance studies which determines the amount of calcium consumed that counterbalances the amount excreted in the urine, GI tract and skin.  Balance studies are technically challenging so estimates are the norm.  Neither bone density nor fracture risk were assessed in determining the calcium RDA.  Therefore, calcium RDA is independent of bone calcium density and fracture risk.  It merely determines the amount needed to keep blood calcium constant so that all calcium-dependent activities can continue.

Fall prevent might help reduce fractures

Since dietary and supplemental calcium do not reduce fracture risk, what strategies might diminish risk?  Many fractures result from falls.  Fortunately, fall prevention is achievable.  Activities/strategies that work include 1) balance and resistance exercises to increase body stability and muscle strength (see Blog 2, 3, 5), 2) environmental changes – decrease house clutter, proper lighting, remove area rugs, 3) assure good eyesight and hearing,  4) reduce polypharmacy (use of 4 or more drugs) (see Blog 21) and 5) avoid multitasking when walking.

Conclusions

It is apparent, certainly in community-dwelling older adults, that calcium supplements have no real benefit on bone density or reduction of fracture risk.  Calcium supplements offer only the potential for adverse effects.  Dietary calcium intake also is independent of fracture risk but unlike supplements does not exert adverse events.  Although calcium from a normal healthy diet such as the Mediterranean diet (see Blog 11) will not fortify or compensate for bone loss, it will contribute to an adequate blood calcium level required for maintenance of essential body functions. 

References

1.  Reid IR et al., Calcium supplements: benefits and risks. Journal of Internal Medicine. 2015, 278: 354–368.

2.  Jackson RD et al., Calcium plus Vitamin D Supplementation and the Risk of Fractures. N Engl J Med. 2006; 354: 669-83.

3.  Bollard MJ et al., Calcium intake and risk of fracture: systematic review.  BMJ. 2015; 351: h4580.

4.  Harvey NC et al., The role of calcium supplementation in healthy musculoskeletal ageing: An Experts consensus meeting of the European Society for Clinical and Economic Aspects of Osteoporosis, Osteoarthritis and Musculoskeletal Diseases (ESCEO) and the International Foundation for Osteoporosis (IOF).  Osteoporosis Int. 2017 February; 28(2): 447–462.

5.  Zhao JG et al., Association Between Calcium or Vitamin D Supplementation and Fracture Incidence in Community-Dwelling Older Adults: A Systematic Review and Meta-analysis. JAMA. 2017 Dec 26; 318(24): 2466–2482.

6.  Hu ZC et al., Comparison of fracture risk using different supplemental doses of vitamin D, calcium or their combination: a network meta-analysis of randomized controlled trials. BMJ Open.2019;9:e024595.

7.  Karti K et al.,  Role of calcium &/or vitamin D supplementation in preventing osteoporotic fracture in the elderly: A systematic review & meta-analysis. Indian J Med Res. 158:  5-16, 2023.

8.  Chapuy MC  et al., Vitamin-D3 and calcium to prevent hip fractures in elderly women. N Engl J Med. 1992; 327: 1637–42.

9.  Anderson JJB et al., Calcium Intake From Diet and Supplements and the Risk of Coronary Artery Calcification and its Progression Among Older Adults: 10-Year Follow-up of the Multi-Ethnic Study of Atherosclerosis (MESA) J Am Heart Assoc. 2016;5:e003815.

10.  Yang C et al., The evidence and controversy between dietary calcium intake and calcium supplementation and risk of cardiovascular disease:  A systematic review and meta-analysis of cohort studies and randomized controlled trials. J Am Coll Nutr. 2020 May-Jun;39(4):  352-370.

Additional references

11.  Myung SK et al., Calcium Supplements and Risk of Cardiovascular Disease: A Meta-Analysis of Clinical Trials Nutrients 2021, 13, 368.

12.  Mao PJ et al., Effect of calcium or vitamin D supplementation on vascular outcomes: a meta-analysis of randomized controlled trials. .Int J Cardiol. 2013 Oct 30;169(2):106-11.

13.  Pana TA et al., Calcium intake, calcium supplementation and cardiovascular disease and mortality in the British population: EPIC‑norfolk prospective cohort study and meta‑analysis. European Journal of Epidemiology. (2021) 36: 669–683.

14.  Reid IR et al., Randomized controlled trial of calcium in healthy older women. Am J Med.  2006 Sep;119(9):777-85.

15. Reid IR, et al. Randomized controlled trial of calcium supplementation in healthy, nonosteoporotic, older men. Arch Intern Med. 2008; 168: 2276–82.

16. Harris SS ad Dawson-Hughes B. Effects of Hydration and Calcium Supplementation on Urine Calcium Concentration in Healthy Postmenopausal Women. J Am Coll Nutr. 2015;34(4):340-6.

Osteoarthritis – Robber of Mobility and Independence

Individual controls aging, Osteoarthritis, , , ,

Osteoarthritis is a progressive inflammatory-dependent deterioration of one or more joints (knees, hips, hands, elbow, spine) that robs the older adult of mobility and independence.  “Osteoarthritis is the most com­mon form of arthritis, affecting 1 in 3 people over age 65 and women more so than men” (Hawker, 2019).  After diabetes and dementia, osteoarthritis ranks third in disability prevalence among older adults.

Overview

Osteoarthritis, robber of mobility and independence, begins as an illness characterized by joint pain, joint stiffness (especially when sitting for prolonged periods), muscle weakness, and reduced quality of life.  Over time, structural changes develop in potentially all components of the affected joint.  With permanent damage, osteoarthritis progresses to a disease state that severely limits range of motion, especially walking, leading to a serious disability.  Additionally, it reduces exercise ability, fragments sleep, impairs productivity, encourages early retirement and steals independence.  Sadly, osteoarthritis remains a major disability without an approved disease-modifying therapy.  Symptoms may be minimized with over-the-counter pain/anti-inflammatory medications or injections of steroids into the joint (intra-articular).  Eventually, surgical intervention with total joint replacement is required.

Modifiable Risk Factors

There are two modifiable risk factors strongly associated with osteoarthritis.  They are obesity (adiposity) and joint injury (high impact and/or repetitive mechanical stress).  Additionally, there are several non-modifiable risk factors associated with osteoarthritis.  They include age, gender (female), and genetics (skeletal structure and alignment; uncorrected deformities).

The data suggests that maintenance of a normal body weight and reduction of joint injury, for example, in high stress occupations and elite sports, with proper physical preparations (e.g. exercises to strengthen muscles around joints) would reduce the risk of osteoarthritis.  At present, the actual clinical support for this is minimal because there has been little interest, hence few studies. 

One study on the effect of weight loss and exercise on knee osteoarthritis found that those who adhered to the recommended diet and exercise program had a lower incidence of knee osteoarthritis at 30 months out and those that lost 5% of their body weight has reduced joint injury at 6.5 years compared to controls.  On the effect of exercise alone on the prevention of osteoarthritis, there are  a number of clinical trials, but of poor quality.  It appears that prevention of osteoarthritis by reduction of modifiable risk factors has to date received little clinical attention.

However, it is still important to re-emphasize the wealth of clinical data supporting the multiple benefits of exercise (Insight 2: Skeletal muscles, aging and consequences, Insight 3: Ways to retard skeletal muscle aging, Insight 4: Anti-aging benefits of aerobic and stretch exercises).  For example, an exercise program reduces the risks for numerous other morbidities e.g. cardiovascular disease, and diabetes.  A comorbidity with osteoarthritis accelerates joint deterioration.  Exercise also reduces the risk of weight gain, promotes stable movements and stabilizes joints, thereby reducing mechanical stress.

Pathological Changes

There is growing interest in defining the pathological changes that occur during development of osteoarthritis.  This research effort could potentially give rise to novel and effective disease-altering therapies.

Components of the Joint

The joint brings two bones together. The end of each bone is called the subchondral portion.  It is covered by hyaline cartilage (articular) composed of fibrous proteins such as collagen, lots of water, and a few collagen-secreting cells called chondrocytes.  There is no nerve or blood supply or lymphatic drainage making damage repair difficult.  The synovial membrane that secretes the synovial fluid covers the articular cartilage.  Ligaments (bone to bone) and tendons (muscle to bone) secure the joint.

Identified pathology

1)  Breakdown of cartilage – harmful enzymes slowly destroy collagen and other matrix proteins; the low number of chondrocytes retards repair. 

2)  Inflammation in synovial fluid.  Mechanical injury activates innate and immune responses with production of numerous pro-inflammatory mediators that destroy tissue.

3)  Fibrosis – production of extra matrix proteins that contributes to synovial membrane thickness and stiffness.

4)  Subchondral bone changes – bone supporting joint cartilage remodels in unfavorable ways.

5)  Senescent cells – Chondrocytes senesce and exacerbate the inflammation by production of pro-inflammatory mediators and loss of normal function e.g. collagen repair. (See Blog 23 on senescent cells)

Current Therapies

Osteoarthritic pain is generally treated with topical or oral anti-inflammatory drugs.  Specifically, education, exercise programs (strengthening, cardiovascular, mind-body i.e. Yoga) and weight loss strategies are encouraged. If seriously practiced, this approach consistently reduces joint pain. 

As symptoms worsen, intra-articular injections of steroids provide additional relief.  However, progression to structural damage (radiological confirmation) requires total joint replacement called arthroplasty surgery. The consensus to date is that arthroplasty surgery for the treatment of osteoarthritis is a successful therapy.

Future Therapies

Chemical entities that target one of the five pathological changes mentioned above are in development.  Most, such as the senolytics, are effective in animal models of the disease.  A potential future therapy, pirfenidone, an anti-fibrotic drug, used to treat pulmonary fibrosis, may decrease fibrosis in osteoarthritis.  Another future therapy, now in clinical trials for pain relief in osteoarthritis is the intra-articular injections of a growth factor (portion of FGF-18 termed psrifermin).

Another therapy gaining considerable interest is intra-articular injection or implantation of  stem cells.  The approach is to harvest and inject mesenchymal stem cells (multipotent adult cells obtained from tissues such as bone marrow, fat, umbilical cord). In a critique of clinical trials using stem cell therapy for osteoarthritis, Diego de Carvalho Carneiro et al., (2023) reported findings that “indicate that intra-articular injections of mesenchymal stem cells are efficacious in the treatment of osteoarthritis and the regeneration of cartilage, but that they may be insufficient for the full repair of articular cartilage defects.”  Additional large rigorous clinical trials would be of value.

Conclusions 

Osteoarthritis is a debilitating joint illness/disease that robs an individual of independence.  It desperately needs effective disease-modifying therapy.  Fortunately, potentially valuable therapies are on the horizon.  However, until these therapies are validated, it seems reasonable to establish common sense policies for the prevention of osteoarthritis beginning in childhood and continuing throughout the lifespan.  These policies would include the maintenance of normal body weight throughout life, engagement in proven injury prevention for high impact sports and careers and a continuous exercise program to eliminate the development of co-morbidities and assure normal stresses on all joints.

References (Pubmed)

Aubourg G et al., Genetics of osteoarthritis. Osteoarthritis and Cartilage 30:  636-649, 2022.

Diego de Carvalho Carneiro et al., Clinical Trials with Mesenchymal Stem Cell Therapies for Osteoarthritis: Challenges in the Regeneration of Articular Cartilage. Int. J. Mol. Sci. 2023, 24, 9939.

Hawker GA.  Osteoarthritis is a serious disease.  Clin Exp Rheumatol  37 (Suppl. 120): S3-S6,2019.

Jiang  Y et al., Osteoarthritis year in review 2021: biology Osteoarthritis and Cartilage 30 (2022) 207e215

Katz JN et al., Diagnosis and treatment of hip and knee osteoarthritis: A review JAMA. 2021 February 09; 325(6): 568–578.

Kun E et al., The genetic architecture and evolution of the human skeletal form. Science. 2023 Jul 21;381(6655)

Thoene M et al., The Current State of Osteoarthritis Treatment Options Using Stem Cells for Regenerative Therapy: A Review. Int. J. Mol. Sci.2023, 24, 8925.

Vincent TL et al., Osteoarthritis pathophysiology – therapeutic target discovery may require a multi-faceted approach. Clin Geriatr Med. 38(2): 193–219, 2022.

Whittaker JL et al., A lifespan approach to osteoarthritis prevention. Osteoarthritis and Cartilage 29 (2021) 1638e1653

Frailty Syndrome – how to modify

Individual controls aging, ,

Introduction

The Frailty Syndrome is one of several geriatric syndromes that has received recent attention.  The Frailty Syndrome reduces one’s response to stress thereby enhancing the risk of dying.  Importantly, the Frailty Syndrome is potentially modifiable.  Although an official consensus definition of Frailty Syndrome does not exist, it is generally defined as “a clinical syndrome that leads to a progressive, multisystem decline in function and physiologic reserve, and increased vulnerability to adverse outcomes” (Park and Ko, 2021).

Identification Protocols of the Frailty Syndrome

One of two protocols have generally been used to identify the Frailty Syndrome.  The first is the Fried’s Frailty Phenotype.  It characterizes frailty with the  use of 5 criteria.  They are 1) unintentional weight loss ((≥5 percent of body weight in the past year), 2) self-reported exhaustion, 3) low grip strength, 4) slow walking speed  and 5) low physical activity.  Individuals diagnosed with 3 or more of the  5 conditions are considered frail and at risk of a 2 fold increase in morbidity and death.  However, expression of one or two criteria is deemed pre-frail and predicts an enhanced risk of progression to greater frailty.  Older adults without any of the above characteristics are non-frail or robust.

The second protocol is the Frailty Index.  The Frailty Index seeks to assess vulnerability based on a wide range of age changes to include disabilities, disease states, functional and cognitive deficits and psychosocial factors.  Some 30-40 factors may be assessed.  The Index is derived by counting the number of deficits and dividing by the total possible.  The higher the frailty index number, the greater the accumulation of deficits and the greater the degree of frailty.  This relates to an increase in negative outcomes, such as falls, surgical complications, institutionalizations, or worse, disability and death.

A systematic review of community dwelling individuals (65 years and old) indicated that the prevalence of frailty ranges from 4-59.7% depending on the frailty criteria used (Collard et al., 2012).  Although frailty increases with age and is a burden on healthcare costs, there are interventions validated by clinical trials that can prevent and/or ameliorate frailty.

Origins of Frailty Syndrome

Several organ systems contribute to frailty.  A major contributor is the significant changes that occur in the endocrine system with age.  These changes include a major decline in levels of hormones e.g. growth hormone, insulin-like growth factor-1 (a growth hormone assistant) and some adrenal steroids such as DHEA (dehydroepiandrosterone).  In contrast, another adrenal steroid, cortisol, increases (see Blog 19). These hormones play key roles in muscle maintenance and coupled with an absence of resistance exercises, permit loss of muscle mass and strength (see Blog 2,3). 

Another factor is inflammaging, a condition of low grade inflammation, identified with increased blood levels of pro-inflammatory factors such as ” interleukin 6, c-reactive protein, increased numbers of neutrophils and macrophages and activation of markers of clotting cascade” (Park and Ko, 2021).  One of the hallmarks of aging (epigenetic alterations, see Blog 26) fosters inflammaging, a condition of continual organ/tissue degradation.

Interventions for the Frailty Syndrome

Multidisciplinary Intervention – How to modify

There have been many interventional studies seeking to reduce/prevent frailty.  One of the earliest clinical trials to address this goal was the Frailty Intervention Trial (FIT) (Cameron et al., 2013).  This study found that frailty can be successfully treated with an interdisciplinary multifaceted treatment program.  Specifically, 216 participants with frailty (Fried’s Phenotype), average age of 83 years were randomized to receive either multidisciplinary intervention or standard health care for one year.  The multidisciplinary interventions were tailored to the individual depending on the frailty characteristics.  They consisted of, for example, nutritional evaluation and home-delivered meals for weight loss and home-based physiotherapy sessions and home exercise program for weakness, slowness or low energy expenditure.  The trial results showed individualized interventions clearly reduced frailty and increased mobility.

Effective Exercises Modify the Frailty Syndrome

In an assessment of multiple trials, a systematic review of frailty interventions from 46 primary care studies, world-wide concluded that “interventions with both strength training and protein supplementation consistently placed highest in terms of relative effectiveness and ease of implementation” (Travers et al., 2019).  Effective exercises ranged from mild-intensity mixed exercises (e.g. aerobics, resistance) or singular exercises such as walking or tai-chi.  Interventions targeting behavioral changes were easy to implement but of low value.  Home visits, comprehensive geriatric assessment, administration of hormones (testosterone, DHEA) were difficult to implement and also of low efficacy.  Approximately 65% of these studies employed more than one intervention.

Another earlier comprehensive review (12 randomized controlled trials and 2 cohort studies) with the goal of preventing or reducing frailty found interventions that significantly reduced the greatest number of frailty markers were physical exercises (all types and combinations) (Puts et al., 2017).

Specific Physical Activity Modify the Frailty Syndrome

Travers et al., proposes the following physical activity for frailty intervention: “20–25 minutes of activity, 4 days per week at home, comprising 15 exercises: three for strengthening arms, seven for strengthening legs, and five for balance and coordination. Each exercise is repeated 10 times per minute, progressively reaching 15 times after 2–3 months, with a rest of half a minute between each set”. 

Finally, early intervention is highly desirable.  A twenty year longitudinal study of over 6000 adults reported that healthy habits started at a younger age  (age 50) reduce the risk of frailty later in life.  Those habits included 1) not smoking, 2) moderate alcohol consumption, 3) physical activity of at least 2.5 hours per week, and 4)  consuming fruits and vegetables at least twice daily.  Following all 4 yields a 70% reduction in frailty risk.

Conclusions

The Frailty Syndrome is a preventable decline in organ function summating in seriously reduced response to inevitable stresses.  Expert analysis of over 50 clinical studies indicate that a program of physical activity is key in ameliorating frailty.  Where possible an individualized program addressing each frailty component is ideal.

References (pubmed)

Aas SN et al., Strength training and protein supplementation improve muscle mass, strength, and function in mobility-limited older adults: a randomized controlled trial. Aging Clin Exp Res. 32(4):  605-616, 2020.

Cameron ID et al.,  A multifactorial interdisciplinary intervention reduces frailty in older people: randomized trial.  BMC Med. 11:  65, 2013.

Collard RM et al., Prevalence of frailty in community-dwelling older persons: a systematic review. J Am Geriatr Soc . 60(8):  1487-92, 2012.

Fried LP et al.,  Frailty in older adults: evidence for a phenotype. The journals of gerontology Series A, Biological sciences and medical sciences. 56(3):  M146–56, 2001.

Gil-salcedo A et al., Healthy behaviors at age 50 years and frailty at older ages in a 20-year follow-up of the UK Whitehall II cohort: A longitudinal study. PLoS Med. 17(7):   e1003147, 2020.

Kojima G, Liljas AEM, Iliffe S. Frailty syndrome: implications and challenges for health care policy. Risk Manag Healthc Policy. 12:  23–30, 2019.

Park C, Ko FC.  The Science of Frailty: Sex differences. Clin Geriatr Med. 37(4):  625–638, 2021.

Puts MTE et al., Interventions to prevent or reduce the level of frailty in community-dwelling older adults: a scoping review of the literature and international policies. Age Ageing. 46(3):  383-392, 2017.

Rockwood K, Mitnitski A.  Frailty in relation to the accumulation of deficits. J Gerontol A Biol Sci Med Sci .  62(7):  722-7, 2007.

Rockwood K, Mitnitski A. Frailty defined by deficit accumulation and geriatric medicine defined by frailty. Clin Geriatr Med. 27(1):  17–26, 2011.

Roschel H.  et al., Supplement-based nutritional strategies to tackle frailty: A multifactorial, double-blind, randomized placebo-controlled trial Clin Nutr  40(8):  4849-4858, 2021.

Travers J et al., Delaying and reversing frailty: a systematic review of primary care interventions Br J Gen Pract. 9(678):  e61–e69, 2019.

Geroscience – Drugs to Retard Aging

Drugs to retard aging, , , , , ,

Introduction

Geroscience is the rapidly expanding field of gerontology with a specific objective beyond that of understanding aging.  Instead, it is evaluating drugs to retard aging. Specifically, it states that the goals of aging research are “best achieved by novel integrated approaches to health and disease with the understanding that biological systems change with age” (Kennedy et al., 2014).  Since aging is the major risk factor for disease, geroscience recommends that rather than treat age-related diseases one by one, physicians should instead “treat” aging.  Hence, the focus should be to identify future drugs to retard aging.  If age changes are delayed, prevented or reversed, diseases would likewise be delayed.  Therefore, drugs to retard aging would lengthen the healthspan and provide years lived with good health and not in management of disease.

Geroscience proposes the Unified Hypothesis of Aging.  This hypothesis states that all age changes are interrelated.  Thus, according to this hypothesis, pharmacological reduction i.e. drug-dependent reduction of one aspect of aging will decrease the other aspects of aging.  A trans-National Institutes of Health Geroscience Interest Group Summit (2019) established a consensus on age changes.  Age changes are Pillars of Aging or Hallmarks of Aging.  

Hallmarks of Aging

Prominent age changes investigated over the years are identified as follows (Lopez-Otin et al., 2013): 

1.  Loss of genetic stability

Damage to both nuclear and mitochondrial DNA accumulates over the years resulting in a variety of changes (mutations, deletions) that reduces the ability of the DNA to do its job i.e. direct production of proteins.  This loss leads to abnormal cell function and future tissue/organ incompetence.

2.  Reduction in telomere length

This is a popular topic.  Several companies offer services to measure telomere length implying that telomere length is a surrogate of  biological age, that is the longer the telomeres, the younger the individual.  Telomeres are the protein-nucleic acid complexes at the ends of each chromosome.  Telomeres function to prevent the ends from “sticking” together during DNA replication in cell division. With each replication, the length of the telomeres shorten until they are too short to provide protection.  This stops future cell division and prevents the biological advantage of cell renewal.  No new cells are formed.

3.  Epigenetic alterations

These are changes in the expression of DNA.  The structure of DNA i.e. the genetic code is not altered.  In contrast, epigenetic alterations influence which genes are expressed (turned on to make proteins and which are turned off and make no protein).  Epigenetic alterations turn on genes that produce inflammatory proteins and turn off genes that make anti-inflammatory proteins, fostering a state of age-dependent chronic low grade inflammation.    

4.   Loss of protein stability

Proteins require correct folding and appropriate disposal when no longer needed.  The complex systems regulating these activities deteriorate with age.  The result is accumulation of toxic incompetent proteins

5.  Altered nutrient sensing

Nutrient sensing complexes detect high glucose, amino acids and levels of energy.  The most famous nutrient sensor is insulin and its relative, insulin growth factor (IGF).  Moderation and/or suppression of these sensors in animal models of aging increases the healthspan and lifespan.

6.   Mitochondrial dysfunction

Mitochondria are subcomponents (organelles) of the cell and are responsible for generating the main energy molecule, ATP.  Another key function of mitochondria is the ability to generate the signals to terminate the life of a cell in the presence of irreparable damage.  As mitochondria become dysfunctional with age, less energy is generated and cells disappear.

7.   Cell senescence

This hallmark has been previously discussed (see Blog 23).  Cells that experience unusual stress e.g. excessive DNA damage, high levels of growth factors, repetitive cell division, mitochondrial dysfunction may become senescent.  Senescent cells enlarge, are hypermetabolic producing unwanted negative factors and resist cell death by inhibiting all mechanisms for cell suicide.  They accumulate with age and accelerate aging.  

8.   Stem cell exhaustion

At younger ages, damaged cells generally disappear by programmed cell suicide. Stem cells, pluripotent cells that become any cell type given the correct niche and support factors, come to the rescue.   With age, stem cell number and functionality decline. Lost cells are not replaced and tissues and organs must function with reduced cell numbers.

9.  Abnormal intercellular communication

Communication among cells is facilitated in large part by circulating factors such as hormones and small molecules secreted by immune cells.  Both of these sources diminish with age.  This weakens communication between cells and disrupts organ function.

Drugs to Retard Aging

There is a flourishing number of compounds with potential to inhibit the hallmarks of aging and extend the healthspan in humans.  The majority of these compounds are repurposed drugs.  They include metformin (antidiabetic), rapamycin (immunosuppressant), anticancer drugs quercetin, dasatinib, and fisetin and resveratrol (OTC supplement).  Treatment of animal models of aging (roundworm, flies, mice) with these drugs has produced spectacular results.  These are 1)  rejuvenation of aged organs, 2) reversal of decline in exercise capacity and cardiopulmonary, and metabolic function, 3) delayed onset of disease, and 4) significant extension of maximal lifespan. 

These drugs are now under investigation in man.  Several pilot studies and phase 1 clinical trials have been completed and many more are in the early stage of recruitment.

Resveratrol

Probably the most famous anti-aging drug is resveratrol, a naturally occurring compound extracted from Veratrum grandiflorum (flowering herb), grapes, wine, and soy.  In clinical trials ranging from a few days to months (doses 5 -5000 mg), obese participants experienced consistent reduction in body weight, and lowering of systolic blood pressure and blood sugar.  Several more potent analogues of resveratrol have undergone clinical testing with modest anti-inflammatory and lipid lowering effects.  To date,  the variable pharmacokinetics of resveratrol analogues hindered the expected efficacy seen in animal studies.

Dasatinib and Quercetin

In contrast to the very modest effects of resveratrol analogues, dasatinib (D) and quercetin (Q) (given together intermittently, 3 days for 3 weeks).improved physical function of walking distance, gait speed and chair-stands in 14 elderly patients with pulmonary fibrosis.  A second pilot study administered D+Q for 3 days to 9 patients with diabetic kidney disease. Eleven days post treatment there was a reduction in senescent cells in tissue biopsies of fat, skin and blood.  Undesirable factors known to be secreted by senescent cells were also reduced.  Additional trials are in progress to test the efficacy of D+Q and related drugs in chronic kidney disease, Alzheimer’s Disease, osteoarthritis, and frailty.

Rapamycin

As of April 2023, there are 7 clinical trials evaluating rapamycin as an inhibitor of hallmarks of aging.  These are small placebo controlled trials (34-150 participants, age 60-95).  Additionally, eight other trials with rapamycin treatment assessing immune, cognitive and cardiac function and/or physical responses have been completed but with no publications as yet. 

Metformin

Finally, the inspirational drug for the search for anti-aging drugs is metformin.  In 2013, the FDA for the first time ever, approved a clinical trial to retard aging.  Clinicians will treat 3000 subjects for 6 years with a daily dose of metformin or a  placebo with the  goal of delaying the onset of age-related diseases (https://www.afar.org tame trial).  Metformin treatment of animal models of aging reduced several hallmarks of aging and increased the lifespan.  Observational studies reported that older adults taking metformin for diabetes lived longer than their non diabetic counterparts not taking metformin.  Additionally, metformin offers several advantages: it is inexpensive, has few to no side effects, and has been on the market for more than 20 years with an excellent safety record.  Sadly this study has yet to start due to lack of public funding.

Critique and Considerations

Although there are numerous small pilot studies in the works as well as many completed studies, this is really only the beginning, albeit a remarkable endeavor.  In general, the success of some pilot studies suggests that the hypothesis of retarding the hallmarks of aging is worth pursuing.  However, these initial studies are of short duration and provide no information on long term adverse or toxic effects.  Therefore, larger and longer studies are essential but as with the metformin trial, serious financial support will be difficult to find.   Even clinical success of a repurposed drug offers little monetary reward for a multimillion dollar investment in a large long term clinical trial.  

Select References

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Kennedy BK. et al., Aging: a common driver of chronic diseases and a target for novel interventions. Cell 159(4): 709–713, 2014. 

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