Category Archives: Individual controls aging

Aging is driven by individual lifestyle choices.

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.

Explaining Life Expectancy

Individual controls aging, Life expectancy, , , ,

Introduction

The most significant achievement of the twentieth century was the near doubling of human life expectancy from 47 to 76 years of age.  Although life expectancy is a demographic value, meaning it is an indicator of population aging, nevertheless, it reveals important aspects relevant to individual aging.  This blog will explain life expectancy with a specific focus on:  its determination and underlying assumption, the reasons for the dramatic increase since the 1900s and its relevance to healthy longevity.

What exactly is life expectancy?

“Life expectancy at birth represents the average number of years that a group of infants would live if the group was to experience throughout life the age-specific death rate present at the year of birth” (Murphy et al., 2013).  The unmet assumption lies right in the definition which states that the age-specific death rate at birth remains unchanged throughout life.  But since age-specific death rates change constantly throughout life, life expectancy, at best, represents an estimate of one’s possible lifespan.  Despite the unmet assumption, life expectancy also denotes the health of a population.  Accordingly, the US ranks 29th out of 38 similar developed countries in life expectancy (Organization for Economic Co-Operation and  Development, 2019).  Sadly, the US spends almost twice as much on healthcare compared to the average spending of the top ten countries with higher life expectancies (e.g. Norway, Australia, UK, Switzerland). (https://www.commonwealthfund.org/publications)

Given its less than rigorous premise, life expectancy, however, consistently reveals an unexplained gender gap in which life expectancy of females exceeds that of males by approximately 4-5 years (topic of a future blog).  As of 2021 (Arias et al., 2022), life expectancy was 79.1 years for females, 73.2 years for males and 76.1 years average of both genders.  Secondly, in recent years, life expectancies of subpopulations based on Hispanic origin and race show significant differences.  Specifically, life expectancy (average of both genders) is highest for Asians (83.5 years), followed by Hispanics (77.7 years), Whites (76.4 years), Blacks (70.8 years) and American Indians/Alaska Native (65.2 years).  

Doubling of life expectancy and recent changes

First Half of Twentieth Century

The greatest improvement in life expectancy occurred in the first half of the twentieth century.  This resulted from societal advancements in the handling of sewage, sanitation, and clean water which came about after acceptance of the Germ Theory of Infections proposed by Louis Pasteur, Robert Koch and others.  The Germ Theory of Infections also opened the way for the development of vaccines for diphtheria, whooping cough and tetanus and the launch of sulfa drugs and antibiotics e.g. penicillin.  Together, these changes decreased the mortality rate of infants and children, allowing them to survive to older ages, pushing life expectancy up.

Second Half of the Twentieth Century

The second half of the twentieth century also contributed to increasing life expectancy but in different ways and to a lesser extent.  There was a decrease in infant mortality with acceptance of hospital births favored over home births.  However, more significantly, there was a decline in mortality rates among older individuals due to several developments.  First, protocols for long term management of chronic diseases were established, especially for cardiovascular disease, the major killer of the elderly.  Specifically, identification of more effective drugs, implantable medical devices (pacemakers, stents, defibrillators) and safer surgical procedures added years and increased life expectancy in the US population.  Secondly, access to Medicare and Medicaid provided affordable health care for many. Thirdly, a scientific focus on aging ushered in effective lifestyle choices to maintain the healthspan and decrease mortality.

2014 to 2017

Life expectancy peaked in 2014 at 78.9 years (average of both genders).  A slight decrease in life expectancy occurred from 2015-2017 and might not be significant except for the fact that even this small decline was, unprecedented and due, unfortunately, in large part to an increased mortality rate in young individuals from drug overdoses (opioids), suicides, homicides, and an uptick in deaths in older adults due to Alzheimer’s and cardiovascular disease (Harper et al., 2021). 

2020-2021

Life expectancy experienced a sizeable (0.9-1.8 year) decline in 2020 (77 years) and 2021 (76.1 years), considered the biggest two-year decline in life expectancy since 1921-1923 (CDC National Center for Health Statistics).  This decrease in life expectancy is no surprise.  It resulted from the spike in deaths due to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), better known as the COVID-19 pandemic.  Sadly, many of the negative factors identified in 2015-2017 such as drug overdoses remained an additional contributing factor to the decline in life expectancy in 2020 and 2021. 

Significance of life expectancy to aging

From the discussion above, it is evident that many incredible societal and medical advances have removed environmental hazards, thereby, permitting individuals to reach older ages and in some cases approach the true life span (~119 years of age) of man.  Despite this, the rate of aging in humans has not changed.  In fact, if the life expectancy graphs are transformed to yield a value called the mortality rate doubling time for humans, it is apparent that from the 1900s onward, the mortality rate doubling time remains constant at 8 years beginning at puberty (lowest mortality rate).  Since the mortality rate at puberty is extremely low, doubling that every 8 years gets one to about 119 years of age, which is the oldest validated age reached by humans.

Life expectancy and lifespan

Life expectancy relates to the characteristic human rate of aging. The rate of aging relates to survival, hence lifespan and longevity.  While the human-specific mortality rate signifies inevitable physiological deterioration, it does not mean that aging is biologically programmed.  Far from it, no master “age-directing” programs (genetic or otherwise) are known to exist.  Aging is highly variable from one person to another exactly because it results primarily from environment  factors (e.g. lifestyle choices) and the complex interaction of the environment with our genes (see Insight 1).   

Gerontological investigations show that age changes accrue due to the slow loss of stress resistance, also referred to as loss of essential maintenance and repair mechanisms. Lifestyle choices that optimize those systems of maintenance and repair minimize aging.  Previous blogs discuss many of these lifestyle choices, in particular the 4-prong exercise program (aerobics, resistance, balance, stretch)(see Insight 2; Insight 3: Ways to retard skeletal muscle aging ; Insight 4: Anti-aging benefits of aerobic and stretch exercises; Insight 5 – Optimizing Balance) enhance these maintenance and repair mechanisms to optimize stress resistance.

Expansion or Compression of Healthspan

Does the increase in life expectancy (longevity) evident over the last 100 years come with extra years of health (absence of disease and disability) or with an extension of disease and disability (extended senescent span)?  At present there is no consensus on an answer. This is because there is no agreement on a) exactly what is an age-related disease, b) whether disease is more important than disability and c) how to quantify the social/psychological impact of disease/disability on quality of life.  However, if one considers the ongoing effort of the scientific community to precisely define biological pathways involved in aging and to validate, through clinical trials, effective ways to minimize aging, it seems that each individual should be able to achieve extra years with health rather than with disease and disability.

Change in Life Expectance from 1900 to the Present
References

Arias E, Tejada-Vera, Kochanek KD, hmad FB.  Provisional Life Expectancy Estimates for 2021. Vital Statistics Surveillance Report, August 2022. https://www.cdc.gov 

Harper S, Riddell CA, King NB.  Declining Life Expectancy in the United States: Missing the Trees for the Forest. Annu. Rev. Public Health  42:381–403, 2021

Murphy SL, Xu J, Kochanek KD. Deaths: final data for 2010.  Natl Vital Stat. Rep 61: 1-118, 2013.

Vitamin-mineral supplements: Are they beneficial?

Individual controls aging, Insight 24 - Supplements, , ,

Introduction

Are supplements of vitamins and minerals beneficial? Approximately 80% of the elderly (60 years and older) regularly consume vitamin and mineral supplements without understanding whether such supplements are beneficial or harmful.

There are several reasons for the high consumption of vitamin and mineral supplements by the older adult.

 a)  There is a widespread unfounded concern that their current diet may be deficient in vitamins and minerals, hence necessitating supplements. 

b)  There is a desire to reduce the risk of disease such as cardiovascular disease and cancer.  Vitamin and mineral supplements are believed to lower this risk. 

c)  There is the common wish to forestall age changes such as cognitive decline.  As promoted in advertisements, supplements may minimize age changes. 

d)  Then there is the only demonstrated reason for taking vitamin and mineral supplements and that is to treat a known vitamin/mineral deficiency arising from disease, frailty, chemotherapy or an incredibly poor diet.

This blog will discuss the findings that show

1.  vitamin and mineral supplements do not decrease disease risk or age-related changes,

2.  that most diets supply adequate amounts of vitamins and minerals and

3.  only documented vitamin and mineral deficiencies should be treated with supplements.

Background

Vitamin and mineral supplements are classified as dietary supplements.  Dietary supplements are essentially ingested ingredients intended to supplement the diet (https://www.fda.gov/). Other dietary supplements include herbs and botanicals, probiotics, amino acids, to name a few.

The FDA loosely regulates dietary supplements.  Regulation covers the right to examine manufacturing facilities, handle complaints of adverse effects, and receive required notification for new supplements not found in food.  However, the FDA does not assess dietary supplements for safety or efficacy as required for a new drug prior to marketing.  Essentially, dietary supplements are regulated as a special category of foods.  Certain health claims are permitted as long as the supplement displays the FDA’s disclaimer that the product has not been evaluated by the FDA and is not intended to diagnose, treat, cure or prevent disease.  Thus, it is the manufacturer of the supplement that determines the quality and quantity of dietary supplements.

The dietary supplement industry is a multibillion dollar industry with projected continued growth. Ironically, it is especially lucrative in developed countries where there is an abundance of nutritious and fortified foods.  The most popular dietary supplements in the US are the vitamin/mineral supplements, followed by vitamin D, then omega-3 fatty acid, calcium and vitamin B12 (Mishra S et al., 2021).  

Vitamin and mineral supplements do not decrease the risk of disease.

The diseases in question are non communicable age-related diseases: cardiovascular disease, cancers, diabetes, and chronic kidney disease. 

The conclusion derived from results of the most rigorous clinical trials to date is that use of vitamin and mineral supplements, together or individually (for up to 16 years or more) do not decrease the risk of cardiovascular disease (and associated events e.g. stroke), cancer, type II diabetes, chronic kidney disease and all-cause mortality (Fortmann et al., 2013; Semsek et al., 2021; O’Connor et al., 2022). 

Study Details

The reviews cited above critiqued hundreds of relevant clinical studies, selecting those with definitive objectives and measurable endpoints.  Study duration ranged from 3 to 36 years with most under 10 yrs. Vitamins and minerals were either commercially available multivitamins or select vitamins and minerals prepared by the principal investigators.  These studies enrolled healthy adults without nutritional deficiencies.  Some early studies reported beneficial effects of vitamin and mineral supplements on disease risk but as the authors point out, these were observational studies that cannot control for confounding factors such as randomization of participants.  As a result of this flaw, the observed positive effects of supplements in observational studies cannot be separated from other significantly influencing factors such as  lifestyle choices of physical exercise and healthy eating.  

Reported Harm

It is noted that two clinical trials reported a borderline statistical decrease in cancer risk in men taking multivitamins and minerals (Hercberg et al., 2004; Grazino et al., 2012).  This minor effect, evident only in men, was not strong enough to alter the main conclusion that use of vitamin and mineral supplements do not provide a health benefit regarding disease suppression.  Furthermore, some vitamins alone or in combination actually increased risk of lung cancer.  Specifically, several trials showed increased lung cancer risk with use of beta-carotene (converted to vitamin A in the body)  alone or in combination with vitamin A and an increase in prostate cancer in smokers using vitamin E (Zhang et al., 2020).

Vitamin and mineral supplements do not reduce age-related changes.

A comprehensive literature addressing this issue does not exist at present.  Here is the current understanding.

Aging of Bone 

Vitamin D is an important player in maintaining bone density and hence optimizing bone strength to prevent breakage from a fall.  However, the body receives vitamin D from many sources such as sunshine-dependent synthesis in the skin and kidney, from a number of foods (tofu, seafood) and with consumption of fortified cereals and juices.

A recent review (Giustina et al., 2022) published a consensus statement that after reviewing the best studies to date, found that with the exception of house-bound or nursing home residents, the elderly receive sufficient amount of vitamin D from diverse sources mentioned above and hence do not need vitamin D supplements.  However, if in doubt, a simple blood test can determine whether the vitamin D level is at adequate (established range 30 to 50 nmol/L; 12–20 ng/mL).

Aging of the brain 

Although there are many proven ways to optimize cognitive function (see Insight 6 – More longevity building: Ways to minimize brain aging), older adults obsess about their mental acuity.  Two studies (Grodstein et al., 2013; Baker et al., 2022) examined the effect of daily use of a commercially available multivitamin (containing minerals).  The first of the two, the Physicians’ Health Study II measured cognitive function 4 times over a 12 year period. 

Nearly 6000 males ≥ 65 years (included nearly 6,000)participated in the first study.  This study found no effect of supplements on cognitive test scores.  The second study was smaller with a test group of 500 participants. This study included both men and women and assessed cognitive function annually over a 3 year period.  This study concluded that global cognitive scores improved with supplementation. 

Whether supplements benefit the mind remains unresolved with these conflicting results. However, there are some interesting aspects to these two studies.  Both studies, although using comparable and acceptable cognitive tests, measured cognitive function over the telephone.  The investigators indicate that telephone testing is less expensive and yields the same results as in-person testing.  The reference for this was the comparison to in-person test results of 24 individuals.  Secondly, there was a expected “practice” effect with repeat testing in both studies.  This means the test scores increase with repeat testing in both the supplement group and the placebo group.  As a result, the benefit reported in the second study on the last round of testing is modest at best.  Whether this small effect will translate into significant mental acuity in daily life was not measured and remains unknown. 

Healthy adults are unlikely to be vitamin and mineral deficient.

The Food and Nutrition Board of the National Research Council determines the recommended dietary allowance (RDA) of essential nutrients including vitamins and minerals (https://www.ncbi.nlm.nih.gov/books/NBK234926).  This board defines RDAs as “the levels of intake of essential nutrients that, on the basis of scientific knowledge, are judged by the Food and Nutrition Board to be adequate to meet the known nutrient needs of practically all healthy persons.”  They also indicate that consumption of a varied diet (“variety of foods from diverse food groups”) achieves the RDA for vitamins and minerals for most adults.   In addition, the availability of fortified foods further assures attainment of the RDA.  

Vitamin and mineral supplements ameliorate confirmed vitamin and mineral deficiencies.

Scientists define nutritional deficiencie as “intake of nutrients that is lower than the estimated average requirement” (Kiani et al, 2022).   Nutritional deficiencies are likely in situations of poor appetite due to medications, frailty syndrome and metabolic diseases limiting nutrient absorption.  Symptoms and low blood concentrations of vitamins and minerals alert the physician to a possible deficiency.  Uncorrected vitamin/mineral deficiencies definitely lead to serious debilitating conditions. They are goiter (iodine), rickets (and osteomalacia) (vitamin D), beriberi (thiamine, B1), pellagra (niacin, B3), and pernicious anemia (B12).  Correcting vitamin/mineral deficiencies under physician supervision is necessary. It should be the only reason older adults should consume select vitamin/mineral supplements.

Conclusions

There is little convincing evidence for the older adult to take vitamin and mineral supplements.  Diets provide adequate amounts of vitamins and minerals and supplements do not lower the risk for age-related diseases.

In place of supplements

To minimize disease risk and age-related age changes, scientist suggest alternatives to supplements that include the following:

a) adherence to the Mediterranean and related diets (Insight 10-Best Longevity diet = Mediterranean Diet), b) commitment to a physical exercise program (Insight 3: Ways to retard skeletal muscle aging Insight 4: Anti-aging benefits of aerobic and stretch exercises, Insight 5 – Optimizing Balance) c)engagement in mentally challenging activities (Insight 6 – More longevity building: Ways to minimize brain aging) and d) adequate sleep (Insight 7 – Brain Health and Sleep).

References

Baker et al., Effects of cocoa extract and a multivitamin on cognitive function: A randomized clinical trial. Alzheimers Dement  Sep 14, 2022.

Fortmann SP et al., Vitamin and Mineral Supplements in the Primary Prevention of Cardiovascular Disease and Cancer: An Updated Systematic Evidence Review for the U.S. Preventive Services Task Force Ann Intern Med.159:  824-834, 2013.

Giustina A. et al., Vitamin D in the older population: a consensus statement Endocrine. Oct 26:1-14, 2022.

Grodstein et al., A Randomized Trial of Long-term Multivitamin Supplementation and Cognitive Function in Men: The Physicians’ Health Study II  Ann Intern Med. 159(12): 806–814, 2013.

Kiani et al, Main nutritional deficiencies. J Prev Med Hyg  63(SUPPL. 3): E93-E101, 2022.

Mishra S et al., Dietary Supplement Use Among Adults: United States, 2017–2018  NCHS Data Brief No. 399, Feb;(399):1-8, 2021.

O’Connor EA et al., Vitamin, Mineral, and Multivitamin Supplementation for the Primary Prevention of Cardiovascular Disease and Cancer: A Systematic Evidence Review for the U.S. Preventive Services Task Force Evidence Synthesis, No. 209 Agency for Healthcare Research and Quality (US);  Jun Report No: 21-05278-EF-1, 2021.

Simsek B. et al., Effects of vitamin supplements on clinical cardiovascular outcomes: Time to move on! – a Comprehensive review. Clinical Nutrition ESPEN 42:  1-14, 2021

Zhang et al., Health effects of vitamin and mineral supplements BMJ  369: m2511, 2020.

Future of Anti-aging Medication: Senotherapy

Individual controls aging, ,

Introduction

Because all of our life phases (birth to adulthood) are driven by genetic programs, one naturally assumes genetic programs dictate age changes.  Sadly, they do not (see Insight 1).  In fact our genes contribute at most, 25% to aging.  Thus, 75% of aging is due to one’s lifestyle choices.

Unfortunately, study results show that only a small percentage of elderly actually practice validated and effective activities to minimize aging.  Therefore, for the majority of elderly, this blog brings deliverance in the knowledge of the rapidly developing pharmacological field of senotherapy, with the purpose to reduce disease risk by retarding aging.  It is hoped that senotherapy becomes a supplement to anti-aging lifestyle choices practiced by the individual.

This blog will discuss senotherapy and its merits.  However, since safe and effective senotherapy is not available today but clearly in expected in the near future, it is worthwhile to review known beneficial and anti-aging lifestyle choices.

Proven Activities to Retard Aging

Until senotherapy is common practice, there are many effective ways to retard aging and hence, reduce the risk for disease.  Some of these activities are: 

Pro-Active

1.  COMMITMENT TO A COMPLETE EXERCISE PROGRAM that includes aerobics and stretch (Insight 4: Anti-aging benefits of aerobic and stretch exercises), resistance exercises (Insight 2), balance exercises (Insight 5) .  Numerous benefits include enhanced blood flow to all tissues, stable heart function, stronger muscles, greater flexibility and balance. These all translate into greater independence, reduced risk of falls and decreased disease risk. Other benefits include improved insulin sensitivity especially benefiting from a program of resistance exercise (Insight 18 Vicious Cycle – Aging and Declining Blood Sugar Control).

2.  ADHERENCE TO THE MEDITERRANEAN DIET, a plant-based diet  reduces risks for many diseases including type 2 diabetes, cardiovascular disease, cancers, Alzheimer’s and Parkinson’s diseases (Insight 10). 

3,  PRACTICE OF POSITIVE NEUROPLASTICITY that consist of a) continual engagement in career activities by not retiring, part time retirement, volunteer work or a new career, b) learning new skills e.g. foreign language or musical instrument, c) maintaining social contacts and d) physical exercise program (Insight 6 ).  These activities promote optimal brain function.

4.  AWARENESS OF SPECIFIC MAINTENANCE/PRESERVATION ACTIVITIES OF SENSORY ORGANS can preserve normal sight, hearing, smell and tactile/proprioceptive senses.  This awareness includes use of reading glasses to correct age-related loss of near vision; avoidance of exposure to chronic loud noises e.g. rock concerts, yard tools, to prevent hearing loss (Insight 16 How to Prevent Hearing Loss ), avoidance of exposure to harsh chemicals e.g. Clorox to prevent decline in smell and routine balance exercises to prime sensory neurons (proprioceptors) in joints, ligaments, muscles (Insight 5 – Optimizing Balance).  Accidents, falls, fuzzy thinking results from diminished sensory function.  Physiologically normal sensory function is essential for independent living.    

Avoidance

1.  CHOOSE ACTIVITIES THAT AVOID THE FOLLOWING:   UVA radiation is a known cause of aging skin and skin cancer.  The risk of both are lessened dramatically with routine use of sunscreens, termed broad spectrum.  Compounds classified as broad spectrum sunscreens specifically block UVA  rays from penetrating deep into the skin (Insight 12 -Ways to forestall aging of the skin). 

2. Avoidance of tobacco smoking is absolutely necessary to prevent accelerated aging and enhanced risk of disease including cardiovascular and cancer diseases.  Each inhalation brings in over 1000 toxins that damage precious molecules e.g. DNA, proteins, and lipids.  There are several ways to quit smoking.  Success can result from use of nicotine replacement therapies such as transdermal nicotine patch, nicotine gum, nicotine lozenge and/or pharmaceuticals such as the anti-depressant, bupropion (Zyban) or partial nicotine agonist, varenicline (Chantix) plus physician support with advice and behavioral therapy.

Anti-aging Medication: Senotherapy

Senotherapy is the pharmacological approach to eliminate or modify aged or senescent cells.  This approach will undoubtedly serve those who choose to ignore the clinically proven activities discussed above to retard aging and reduce the risk for disease.  The validated activities delineated above are critically important because they reduce the stress-related factors that cause a cell to age.

Background on Senotherapy

It has been known for some time now that as one ages, the cells in each tissue begin to change.  They increase in size, cease normal function and become bad actors, producing a myriad number of unwanted substances e.g. pro-inflammatory and other destructive agents that harm near-by healthy cells.  Sadly, senescent cells skirt around the biological mechanisms to identify and eliminate them.  Hence, their presence clearly promotes aging of tissues and sets the stage for the first steps to disease.

In consideration of the serious consequences of persistent senescent cells, research interest in senotherapy has blossomed significantly.  Approximately 12 compounds have been evaluated in aged mice or mouse models of disease.  The results of these studies have in many cases been dramatic with reduction in the number of senescent cells and their debilitating functions.  For example, reports show benefits on improved function in kidneys, skeletal muscles, liver and lungs.  Also reported were reduced inflammation in the brain, and increased skeletal muscle regeneration.  

Pilot Studies in Man

Several small pilot studies in man have used senotherapy in conditions of pulmonary fibrosis, macular degeneration, and cardiovascular disease.  Although the results are promising, caution is needed since these studies were of short duration (days/weeks), included few participants (7-13) and used a single dose.  Future studies will surely address these issues and others such as long term adverse effects.

Summary of discussion on anti-aging strategies. What the individual can do and what might be in the future as an aid.
Anti-aging Strategies

Conclusions

In this rush to pharmacologically retard aging, we should not ignore the wealth of data from clinical trials that already exists to minimize cellular aging as continually discussed in prior blogs.  Senotherapy seeks to develop selective drugs to eliminate or minimize the effects of aged cells.  Scientific interest is high because aging is the main risk factor for disease, so to eliminate age changes will significantly decrease disease incidence. 

Select reference (Pubmed)

Bilder, G. Human Biological Aging: from macromolecules to organ-systems.  John Wiley & Sons Publishers, Hoboken, New Jersey, 2016.

Iftikhar U et al., How to Effectively Help Patients Stop Smoking: A Primer for Cardiologists. Canadian Journal of Cardiology 38: 1442-1445, 2022.

Justice JN et al., Senolytics in idiopathic pulmonary fibrosis: Results from a first-in-human, open-label, pilot study. EBioMedicine 40:554-563, 2019.

L’Hote V. et al., From the divergence of senescent cell fates to mechanisms and selectivity of senolytic . Open Biol. 12: 220171, 2022.

Raffaele M., Vinciguera M. The costs and benefits of senotherapeutics for human health.  Lancet Healthy Longev 3: e67–77, 2022.

West, R.  Tobacco smoking: Health impact, prevalence, correlates and nterventions. Psychology & Health,  32:  1018-1036, 2017.

Importance and Harm of AGEs

Importance and Harm of AGEs, Individual controls aging, , , , ,

Blog 22 Introduction

AGEs, the acronym for advanced glycation end products are heterogeneous chemical entities of utmost importance in aging and age-related pathologies.  These chemical products are generated in the foods we eat and they are also generated in the body.  This blog will describe the importance and harm of AGEs and their role in aging.

Initial Importance and Harm of AGEs

The importance and harm of AGEs begins with their discovery. AGEs (also called glyotoxins) were discovered more than 100 years ago by the French physician/chemist, Louis Maillard.  He studied the non enzymatic oxidation between sugars and proteins which generated final products of dark polymers.  These products were of interest because they were endowed with properties of pleasing aroma and taste, highly desirable in foods.  AGEs are one of the many final products of this oxidation reaction, popularly termed, the “browning” reaction.  The “browning” reaction is familiar as it occurs in all foods subjected to high temperatures and may involve oxidations by sugars not only of proteins but also lipids and nucleic acids. 

External AGEs – Generated in Foods

Foods subjected to high temperatures for short periods of time generate significant amounts of AGEs (see a introductory short list below).  Some examples of foods with high concentrations of AGEs include toast, baked goods, processed foods, and fried, broiled and grilled meats.  Fresh fruits and vegetables contain minimal amounts of AGEs.  In comparison, grilled meats (standard serving size) contain AGEs at  several hundred times the amount found in fresh fruits and vegetables.  Several specific methods (generally targeting N-carboxymethyl lysine) are used to measure the concentration of AGEs in foods. 

Internal AGEs – Generated in the Body

The importance and harm of AGEs continues with the discovery of their internal generation. Thus, in addition to AGEs in certain foods, glycations (oxidation by sugars) also occur in the body at physiological temperatures.  Unlike AGEs generated in foods, AGEs generated in the body require a longer time period of generation (months, years).  However, AGE formation is accelerated by the presence of persistent high levels of blood sugar.  A familiar method that measures internal AGEs is  the A1C .  This test measures the glycation of sugar with the hemoglobin protein.  As such it gives an estimate of blood sugar level over time.  Although results of the A1C test are used to manage diabetes, they also give an indication of the oxidative damage occurring elsewhere to other internal proteins.

Internal Pools of AGEs

The body’s internal pools of AGEs are derived from

 a)  oral intake of exogenous AGEs (10-30% of intake is absorbed by intestines, 30% excreted by the kidneys and 60% remaining, continues to circulate and create problems and

b)  endogenous AGE production driven by persistent elevation of blood glucose (resulting from dietary carbohydrates, stress, lack of exercise) further exacerbated by consumption of fructose (sweetened beverages). 

Importance of Processing of AGEs

Fortunately, the body’s pool of AGEs is moderated by several cellular detoxification mechanisms.  One of the best occurs through the uptake by specialized cells called macrophages.  AGEs taken up by these cells are detoxified and create no further problems.  However, as this pathway becomes overwhelmed, AGEs are free to bind to and activate specific receptors, termed RAGE receptors found on most cells.  Uptake by the RAGE receptor is undesirable because it activates an unwanted  chronic inflammatory response.

Harmful Effects of AGEs

1.  Activation of  RAGE receptors by AGEs initiates an inflammatory response.  Acute inflammatory responses are absolutely essential for wound healing but in contrast, continual low level inflammation as with activation of RAGE receptors is detrimental.  The response produces an abundance of inflammatory mediators such as cytokines which induce constant tissue damage and thus contribute to the pathologies of  atherosclerosis, T2D, uremia and neurodegenerative diseases.  

2.  AGEs formed internally result in cross linkages between proteins.  AGE-dependent cross linkage is abundantly evident in collagen, a long lived support protein found in most tissues. Cross linkage of collagen (or any protein) is harmful because it a) alters structure, b) hinders function and c) results in perturbations of vital matrix, material surrounding cells.  In the case of collagen, cross linkage results in tissue stiffness and hence reduced function in arteries, heart, kidney, bone, and skin. 

Some important consequences of AGEs are

a)   exercise intolerance which means early onset of fatigue during exercise,

b)  development of systolic hypertension where systolic pressure is 160 mm Hg or more and diastolic is less than 90 mm Hg,

c)  eventual heart and kidney failure and

d)  sun-exposed wrinkles and sags. 

Avoidance of AGEs

Clinical trial results have validated ways to reduce AGE accumulation in the body.  These include consumption of a diet low in AGEs, such as the Mediterranean diet (see blog 10), a diet of fruits, vegetables, legumes, grains, nuts and fish, and adherence to cooking practices that favor poaching and steaming generally at low temperatures for short periods in place of oven-frying, deep frying, broiling, and roasting.  Efforts are underway to develop new technologies for cooking foods with minimal generation of AGEs while retaining flavor and taste (a topic of a future blog).  Maintaining a fasting glucose level below 100 mg/dl is also prudent (Blogs 18/19 Vicious Cycle – Aging and Declining Blood Sugar Control; Stress Response and Sugar Control)

Relative Amounts of AGEs in Select Food Items

Conclusions

AGEs are harmful chemical entities.  They are ingested in foods that have been prepared at high temperatures.  They are made internally in the presence of persistent high glucose levels.  AGEs that are not detoxified contribute to chronic inflammation and protein cross linkage, both of which contribute to accelerated aging and disease.  For the present, avoidance of foods high in AGEs and maintenance of  low blood sugar are the best strategies to avoid accumulation and organ damage from AGEs.

References

1.  Vistroli V, DeMaddis D, Cipak A et al.  Advanced glycoxidation and lipoxidation end products (AGEs and ALEs): an overview of their mechanisms of formation.  Free Radical Research 47:sup1, 3-27, 2013

2.  Gill V, Kumar V, Singh K et al.  Advanced Glycation End Products (AGEs) May Be a Striking Link Between Modern Diet and Health.  Biomolecules 9:  888, 2019

3.  Nowotny K, Schroter D, Schreiner M, Grune T.  Dietary advanced glycation end products and their relevance for human health.  Ageing Research Reviews 47:  55–66, 2018.

4. Falavena P et al., Formation of advanced glycation end products by novel food processing technologies: A review. Food Chemistry 393: 133338, 2022

Inappropriate Medications for the Elderly

Adverse Drug Reactions, Individual controls aging, , ,

Blog 21 –  Adverse Drug Reactions, Part II

Introduction

The prescribing of inappropriate medications for the elderly creates for them an unnecessary burden, physically and financially.  As noted in Blog 20, and further described here, prescribing of potentially inappropriate medications is one of several acknowledged reasons for adverse drug reactions (ADRs) in the older adult.  

ADRs are harmful and potentially life-threatening reactions dependent on medication use.  ADRs require readjustment or stoppage of the medication.  The elderly are especially sensitive to ADRs as a result of age changes that affect many aspects of drug handling by the body, comorbidities and multiple drug use (see Blog 20).  Prescribing of potentially inappropriate medications brings with it needless ADRs.  This blog will define inappropriate medications according to the Beers Criteria.  It will also discuss the importance of this topic and reasonable ways to avoid ADRs.

Potentially Inappropriate Medications – Origins

Slightly more than 30 years ago, JM Beers organized a panel of clinical experts to systematically categorize appropriate and inappropriate medications in nursing homes (Beers et al., 1991).  From this insightful investigation developed the Beers Criteria, a thoughtfully researched  and expertly evaluated presentation of drugs considered as inappropriate medications for the elderly.  Experts update the Beers Criteria every 3 years with the most recent update published in 2019 (see references).

Potentially Inappropriate Medications – Reasons for drug selection

Medications on the Beers Criteria are there for several reasons.  These are medications that

a)  on average should be avoided in the elderly due to data on age changes,

b)  are to be avoided in elderly with certain conditions,

c)  have low efficacy and hence the risks outweigh benefits and for which there are safer and more efficacious drugs,

d)  are known to interact poorly with commonly used essential drugs and

e)  require extremely careful dosing due to kidney disease

As with all advice on drug use, there are additional issues to consider.  Over time “inappropriate medications” on Beers Criteria became “potentially inappropriate medications”.  This recognizes the possibility that some patients may do well (efficacy in the absence of expected ADRs) with a drug considered inappropriate and, therefore, the caregiver/patient are the final arbiters.

Potentially Inappropriate Medications – Specific classes and drugs

Using medication data from Medicare Part D participants, Toth et al., (2022) reported that inappropriate medications prescribed most frequently fell into one of the following classes of drugs:  proton pump  inhibitors, benzodiazepines and antipsychotics.  These frequently prescribed potentially inappropriate medications are detailed below. Additional potential inappropriate medications (partial list) are presented in the schematic at the end of the blog.  

Proton Pump Inhibitors

Drugs classified as proton pump inhibitors act by blocking acid secretion in the stomach.  Thus, these drugs are useful in the treatment of acid-related disorders e.g. peptic ulcer, gastric reflux.  Drugs in this class are inappropriate for the elderly for several reasons:  Firstly, chronic use is associated with increased risk of bone loss. This would add to the presence of reduced bone density, common in the elderly.  As bone density decreases, the risk of fracture increases.  Fractures are costly, both financially and physically, limiting mobility and independence. Secondly, chronic acid suppression allows for overgrowth of harmful bacteria and use of proton pump inhibitors is associated with the onset of Clostridium difficile infection, a severe bacterial infection that is difficult to eliminate.  Omeprazole (Prilosec) is a proton pump inhibitor that is frequently prescribed.

Benzodiazepines

Drugs labeled benzodiazepines act in the brain to reduce anxiety and induce sedation.  As such they are anxiolytic and hypnotic drugs.  These drugs are inappropriate in the elderly because they hinder memory and additionally are associated with an increased risk of falls. Reduction of memory at any age is unwanted.    Increased risk of falls is highly associated with a fracture with serious consequences.  Additionally, these drugs are addictive.  Commonly prescribed benzodiazepines are alprazolam (Xanax), and lorazepam (Ativan),

Antipsychotics

Antipsychotics act on the brain to suppress psychosis.  These drugs are also sedating and associated with onset of abnormal muscles twitching.  Their use is inappropriate in psychosis associated with Parkinson’s Disease as they exacerbate the disease-dependent muscular dysfunction.  They are also inappropriate in individuals with dementia or cognitive impairment.  Since these drugs are sedating, they are inappropriate in individuals with a history of falls.  Commonly prescribed antipsychotics are quetiapine (Seroquel) and risperidone (Respirdal).

Future Steps

The prevalence of exposure in the elderly to potentially inappropriate medications varies between ~14% to 41% or more depending on the population under study.  Fortunately, the prevalence of prescribing potentially inappropriate medications has declined a few percentage points from 2013 to 2019 (Clark et al., 2020).  This is an encouraging start.  Additionally, there is effort by the medical community to  educate physicians, pharmacists, all prescribing care givers and patients on this issue.  This should further reduce prescribing of potentially inappropriate medications.

Common Sense Approach to Avoidance of ADRs

  • Non pharmacological interventions should always be tried first (see Blogs 2,3,10,11).  Interventions e.g. exercise and diet are highly successful strategies to prevent and moderate diseases such as Type II  diabetes, hypertension (high blood pressure), and heart disease.
  • Older adults taking medications should establish clear goals and endpoints with their physician and continually re-evaluate them.  Every patient needs to know exactly why the medication is prescribed and what to expect from it, that is, how to know if it is working and therefore, worth taking. 
  • It is important to reduce polypharmacy (simultaneous use of more than 4 medications).  The higher the number of prescribed drugs, the greater the risk for ADRs.  Each patient and physician should review drugs frequently and endeavor to eliminate duplicates, and potentially inappropriate medications and keep only the essential drugs.
  • In reduction of polypharmacy, the usage of some drugs is terminated.  Drug withdrawal should be a serious undertaking.  Dose reduction should always be as slow as possible, extending over weeks and months, thereby avoiding unnecessary ADRs.
  • The actual drug dose is critical to avoiding ADRs.  It is common sense to start with the lowest dose possible and increase slowly, if at all.  The use of higher doses requires convincing justification.
Some Additional Potentially Inappropriate Medications

Conclusions

Based on Beers Criteria, an updated assessment of potentially inappropriate medications for the elderly is available to prescribing caregivers and pharmacists.  Drugs on this list negatively interact with age changes in the elderly and hence are potentially inappropriate medications and are responsible for ADRs.  ADRs can be avoided if physicians as well as the patients are informed about the main causes of ADRs and how to prevent them.

References

2019 American Geriatrics Society Beers Criteria Update Expert Panel.   American Geriatrics Society 2019 Updated AGS Beers Criteria® for Potentially Inappropriate Medication Use in Older Adults.  J Am Geriatr Soc. 67(4):674-694, 2019.

Beers et al., Explicit criteria for determining inappropriate medication use in nursing home residents. UCLA Division of Geriatric Medicine Arch Intern Med.  151(9):1825-32, 1991.

Clark CM et al., Potentially Inappropriate Medications Are Associated with Increased Healthcare Utilization and Costs. J Am Geriatr Soc 68(11): 2542–2550, 2020.

Croke L. Beers Criteria for inappropriate mediation use in older patients: An update from the AGS. Am Fam Physician. 101(1):56-57, 2020.

Fernandes de Oliveira RMA et al., Potentially inappropriate medication use in hospitalized elderly patients. Rev Assoc Med Bras 68(6): 797-801, 2022.

Fralick M et al., Estimating the Use of Potentially Inappropriate Medications Among Older Adults in the United States. J Am Geriatr Soc. 68(12):2927-2930, 2020.

Toth JM et al., Prescribing trends of proton pump inhibitors, antipsychotics and benzodiazepines of Medicare part d providers. BMC Geriatrics  22:306-321, 2022.

Steinman MA. How to Use the AGS 2015 Beers Criteria – A Guide for Patients, Clinicians, Health Systems, and Payors.  J Am Geriatr Soc. 63(12): e1–e7, 2015..

Drug Use In The Elderly: Adverse Drug Reactions

Adverse Drug Reactions, Individual controls aging, , , ,

Blog 20- Introduction

The elderly use more medications (including prescription drugs, over-the-counter drugs, dietary supplements) than any other age group.  The appropriate use of medications allows the elderly to manage chronic diseases but brings with it the risk of adverse drug reactions (ADRs).  Learning how drugs are processed in our bodies to produce a specific effect is the first step to appreciate the effects of age and disease on drug use and the origins of ADRs. The second step is to apply this knowledge and avoid adverse drug reactions. Both of these issues will be discussed in this blog and the next.

What Are Adverse Drug Reactions ?

An adverse drug reaction is “an appreciably harmful or unpleasant reaction” that occurs with use of a medicinal product and which requires reevaluation of its use” (Lancet 2000 Oct 7;356(9237):1255-9 http://pubmed ).  ADRs range from mild to severe and life-threatening.  They are definitely unwanted effects.  Unfortunately, ADRs have many causes. 

Reasons for Adverse Drug Reactions in Elderly

ADRs are more severe and frequent in the elderly compared with younger individuals.  Furthermore, ADR severity and frequency increases directly with the number of drugs consumed daily.  As noted above, drug use in the elderly is higher than any other age group.  Reasons for ADRs are numerous.  They include the following:

1.  Age changes alter how drugs are handled in the body

2.  Disease reduces organ function needed to adequately process drugs

3.  Use of multiple drugs has high potential for harmful interactions

4.  Over-the-counter compounds are used inappropriately with prescription drugs  

5.  Inappropriate prescribing by physicians    

Issues 1-4    

Issues 1-4 favor two unwanted outcomes.  Firstly, they influence the concentration of the drug in the blood, causing it to be too high or too low (i.e. outside of the therapeutic window of efficacy).  When a drug’s level is too high, unwanted and possibly life-threatening effects occur and when the drug level is too low, there is no effect and the disease progresses unhindered. Secondly, issues 1-4 also  may hinder a drug’s ability to produce its desired effect, irrespective of drug concentration.  Consequently, when a drug cannot produce its effect, the disease remains untreated. 

Issue 5

Issue 5 relates to taking a drug which is known to exacerbate age-related changes and therefore, should not be prescribed for the elderly.  There exists an extensive list of these drugs, ranging from antispasmodics to antipsychotics (Expert Panel: J Am Geriatr Soc. 67(4):674-694, 2019 http://pubmed).  Unfortunately, many physicians still prescribe them to the elderly.  Issue 5 will be discussed in detail in the following blog.

1.  Age Changes May Influence Adverse Drug Reactions

Principles of pharmacokinetics (PK) and pharmacodynamics (PD) determine how our bodies handle drugs.  Specifically, principles of PK describe absorption of a drug from the GI tract (and other sites), distribution by the circulation to the tissues, metabolism by liver enzymes and excretion by the kidneys.  Principles of PD explain how a drug works at its target site.  In particular, PD explains the ability of a drug to bind to and activate a specific target called a receptor (generally a protein, enzyme or other cell structure) and as a result of these activities, initiates a cascade of subsequent events to produce the predicted therapeutic effect.  Thus PK explains how a drug gets to its target site and PD explains how it works at the target site. 

How drugs are handled in the body

1a.  In general, effects of age on PK are modest but still important.

Absorption:   

Absorption of drugs, regardless of route (gastrointestinal, intravenous, intramuscular or transdermal), remains stable with age.  Other factors such as disease, and  multiple drugs use alter absorption. 

Distribution: 

Once  absorbed and in the circulation, the distribution of a drug is likely to be influenced by age.  This is because, on average, the elderly have more body fat (20-40% more accumulated over time) and 10% less body water.  With increased body fat, drugs with chemical characteristics of high lipid solubility, e.g. anesthetics and hypnotic-sedative drugs take long to equilibrate (saturate the fat depots) and longer to be eliminated.  This means that it takes a longer time for these drugs to take effect and conversely for their effects to dissipate.  A delay in elimination (of anesthetics) is of concern during major surgery since the delay can result in lower oxygen levels, tissue damage and, possibly, pneumonia.

Metabolism: 

The major site of metabolism of drugs is the liver.  Liver enzymes change the chemical structure of the drug.  This results in assured excretion by the kidneys and termination of the drug’s effect.  Findings from recent studies indicate that with age, even in the absence of disease, detrimental structural changes occur in the liver.  Consequently, age-related reduction in blood flow through the liver and reductions in drug metabolism set up the possibility for drug levels to remain higher than expected for long periods of time.  This can result in ADRs.  A simple blood test that measures key liver enzymes determines liver function.  Hence, reduced liver function requires use of lower drug doses.

Elimination:

The kidneys are the major site of elimination of most drugs  As kidney function declines, drug elimination is impaired, resulting in a higher than required drug level.  Thus, ADRs are likely.  Kidney function may decrease with age.  Structural changes that decrease kidney function in the elderly have been reported.   Therefore, it is important that prior to drug use, kidney function is assessed.  A blood test (usually part of the metabolic panel) measures a value called creatinine which indicates the level of kidney function.  Low kidney function requires use of a lower drug dose.

1b.  Significant PD changes occur with age. 

Drug absorption and distribution assure that a drug arrives at its site of action i.e. the select receptor or enzyme.  The binding of drug with its target site leads to the needed therapeutic effect.  With age, receptors may disappear or change in sensitivity.  Specifically, a class of receptors termed beta-adrenergic receptors diminish in number and responsiveness with age.  Hence, drugs that block these receptors, such as antihypertensives and bronchodilators should be avoided.  Use of antihypertensive drugs in this class would produce serious cardiovascular effects and promote imbalance that may lead to falls.  Additionally, bronchodilators of this class are ineffective in the elderly.  Age-related receptor alterations in the brain also make the use of benzodiazepines (hypnotic-sedative) and antipsychotics of questionable value in the elderly.

2.  Effect of Disease on Adverse Drug Reactions

Disease has the potential to create ADRs.  This is especially true for cardiovascular, liver and kidney disease, since they directly influence distribution, metabolism and elimination of a drug.  As noted above, optimal kidney and liver function are required to metabolize and excrete drugs so as to maintain therapeutic levels.  Kidney and liver disease dramatically alter this.  Therefore, kidney and liver diseases require careful selection of drug and dose.  Additionally, adequate blood flow is also important to assure drugs reach their designated targets.  Cardiovascular disease  reduces blood flow slowing the onset time of drug action and reducing time of offset.

Summary: Age and disease influence how drugs are handled in the body

3.  Polypharmacy produces ADRs

Comorbidities of the elderly require multiple drug use.  Use of 4 or more drugs is termed polypharmacy.  It is a significant factor favoring adverse drug reactions (ADRs).  Polypharmacy facilitates ADRs because many drugs use the same liver enzyme for metabolism.  When this happens, the enzymes metabolizes only one drug.  The consequence is that competition for metabolism allows some drugs to remain untouched and so drug levels rise causing toxicities.  Two or more drugs may also compete at the same receptor either in an additive or competitive fashion.  Either way, poor efficacy and ADRs will result. 

Polypharmacy may arise as a result of duplicate medication.  Generally, comorbidities require multiple physicians with different specialties.   If the patient does not fully denote their entire list of medications, physicians may prescribe comparable drugs but with different names.  ADRs are sure to follow.

4.  ADRs with over-the-counter (OTC) products

The combination of  OTCs with prescription medication is problematic.  Firstly, most OTCs are not FDA approved (e.g. have never undergone a controlled clinical trial).  Secondly, quality control of OTCs is unreliable or nonexistent.  Thus, one batch of OTCs may differ radically from another and may also contain contaminants.  Thirdly, the liver metabolizes OTCs, same as prescription drugs and will compete with prescription drug metabolism as noted above.  Thus, OTCs are essentially drugs but without any assurance of amount, efficacy and purity (see Blog 17).  The combination of OTCs with prescription medication is an important topic for discussion with a physician.  Sadly, many elderly do not mention OTC use to their physicians.  The result may be an unnecessary ADR.

Potential Causes of Adverse Drug Reactions

Conclusions

There are numerous  causes of adverse drug reactions in the elderly.  Some ADRs result from changes in blood flow, and liver and kidney function due to age and disease. Physicians know this information and should prescribe accordingly. Additionally, ADRs arising from polypharmacy and OTC use should not be surprising.   They too are avoidable but sadly, they still occur.

My next blog will discuss inappropriate prescribing and common sense means to avoid ADRs. 

Stress Response and Sugar Control

Individual controls aging, , , ,

Blog 19 – The elderly face two distinct hurdles to maintain normal levels of blood sugar (glucose). 

These obstacles  are age-related

   a) loss of skeletal muscle mass and

   b) an aberrant stress response. 

The previous blog  discussed age-related loss of skeletal muscle mass and its influence on glucose levels (see Vicious Cycle – Aging and Declining Blood Sugar Control).  This blog will discuss how age-related changes in our stress response adversely affect our glucose level.

Background – The Stress Response

To adjust to stresses (real or perceived threats) in our lives, humans adapt by activation of several excellent physiological mechanisms, one of which is the stress response.  The stress response is familiar to all.  It is basically described as a “fight or flight” response.  When threatened, the stress response kicks in. The result is enhanced awareness (brain/sensory activation) and accelerated functions of several organ-systems.  This enables one to “run away or stay and fight”.  Once the threat has passed, the stress response dissipates and organ-systems settle back to normal.

In biological terms, the stress response sets off a coordinated activation of multiple key systems e.g. cardiovascular, skeletal muscles and nervous systems.  Importantly, stress triggers the brain (hypothalamus and pituitary glands) to stimulate production and release of a main stress hormone, cortisol from the adrenal glands.  Because these 3 glands work together, they are referenced as the hypothalamic-pituitary-adrenal axis or HPA axis.  Stress also activates the sympathetic nervous system to maximize blood flow to the brain, heart and skeletal muscles.

Cortisol, the “stress” hormone, acts in many ways.  

Firstly, cortisol assures the requisite supply of energy-bearing nutrients e.g. glucose and fatty acids to the brain.  It does this by stimulating the liver to produce glucose and fat depots to release fats.  It also seriously reduces the effects of insulin so that blood glucose remains abundantly high for the needs of the brain, an organ not requiring insulin for its uptake of nutrients, including glucose. 

Secondly, cortisol partners with the sympathetic nervous system to assure optimal heart, muscles and brain function.  Together, these actions ready the individual to handle stress.

Thirdly, there exist several inhibitory mechanisms that limit the duration and extent of the stress response.

This is a good thing since continued presence of cortisol not only adversely affects glucose and insulin levels but also robs calcium from bones and suppresses the immune system.  Regrettably, these effects are more prevalent as one ages.

Effect of Age on the Stress Response

Humans cannot live without cortisol.  It circulates in a rhythmic fashion at low levels 24/7.  The basal concentration of cortisol is highest in the early morning.  Thereafter, cortisol slowly declines throughout the day.  Its lowest level occurs late in the night.  Stress significantly and transiently elevates the concentration of cortisol above basal values to achieve the “flight or fight” response. 

Daily output of cortisol increases

Unlike most other hormones e.g. growth hormone, melatonin, estrogen, that decline dramatically with age, the daily output of cortisol increases with age.  This was convincingly confirmed in a lifelong (20-90 years of age) longitudinal study. This study measured 24 hour urinary output of cortisol (normalized to kidney function). It included over 1800 male and female volunteers in the Baltimore Longitudinal Study of Aging (Moffat et al., 2020).

Basal rhythm exhibits elevated levels

Secondly, not only is total production of cortisol increased with age, but the basal rhythmic pattern is maintained at a significantly higher level throughout the day in the elderly compared to young adults.  By sampling cortisol levels every 15 minutes or so over a 24 hour period, many small studies provide data supporting this conclusion.  Thus even at rest, cortisol levels in the elderly are elevated.

Response to stress is more forceful and persistent

Thirdly, the stress response is exaggerated in the elderly.  Activation of the stress response in the elderly results in an age-related elevation of cortisol and a prolongation of the response.  This is supported by a meta-analysis of 48 small studies in which cortisol levels were assessed following a physiological or psychological stress in young and elderly individuals (Otte et al., 2005).  A meta-analysis selects similar publications based on rigorous criteria. It then statistically combines all study results to achieve a composite statistic with a greater level of confidence.  According to this meta-analysis, “older participants showed either increased cortisol secretion or reduced cortisol inhibition in response to a physiological or psychological challenge.”

In other words, in the elderly, cortisol levels are higher for longer periods thereby ensuring higher levels of glucose and extended inhibition of insulin.  This puts the elderly at a disadvantage, creates an inability to regulate blood glucose and increases the risk for type II diabetes..

Relaxation Techniques in Preliminary Stages

There is a wealth of data confirming the benefits of progressive resistance exercise. It is a proven way to maintain muscle mass with age and hence preserve control of blood sugar. In contrast, the data identifying a successful strategy to reduce an augmented stress response as well as elevated basal cortisol levels are essentially preliminary.  Of considerable interest are techniques of a) yoga  and b) mindfulness-based stress reduction.

A meta-analysis reviewed 42 small clinical trials in individuals practicing yoga. The trials used appropriate controls and objective  measures (e.g. cortisol concentrations, blood pressure, other stress factors).  The analytical results concluded that the practice of yoga is “associated with improved regulation” of cortisol (hypothalamus-pituitary-adrenal axis) and the sympathetic nervous system”(Pascoe et al., 2017).   

Only a handful of clinical trials included in the Pascoe et al., (2017) meta-analysis included volunteers over the age of 65.  Of these, only one measured cortisol levels; the others measured blood pressure changes before and after yoga therapy.  With this limited data, all objective measures and subjective measures (perceived stress) were lowered with the practice of yoga in the elderly.

Mindfulness-based stress reduction is a clinically standardized type of meditation. Unfortunately, there is only one controlled study on the effect of mindfulness on objective measures of stress in healthy elderly.  A small study assessed a 3-day retreat of intensive mindfulness compared to a 3-day vacation (Gardi et al., 2022). The former produced better stress reduction regarding perceived anxiety, lower cortisol levels and lower levels of inflammatory factors.

Conclusions

As one ages, it becomes more difficult to maintain glucose levels in an optimal range.  This is partly due to the age-related exaggeration of the stress response.  The stress response serves us well in our youth. However, modifications that occur with age e.g. higher and persistent levels of cortisol, allow glucose to achieve a stronger and longer presence.  These changes create the milieu for prediabetes, elevate the risk for type II diabetes and accelerate normal aging through oxidation.  Sadly, potential means to minimize the aberrant stress response e.g. yoga and mindfulness lack adequate evaluation.  Large controlled clinical trials with the elderly are sorely needed.

Select References

Gardi C. et al., A short mindfulness retreat can improve biological markers of stress and inflammation. Psychoneuroendocrinology. 135:  105579, 2022.

Moffat SD et al.,  Longitudinal Change in Cortisol Levels Across the Adult Life Span. J Gerontol A Biol Sci Med Sci. 75:  394–400, 2020.

Otte C et al., A meta-analysis of cortisol response to challenge in human aging: importance of gender. Psychoneuroendocrinology 30:  80-91, 2005..

Pascoe MC et al., Yoga, mindfulness-based stress reduction and stress-related physiological measures: A meta-analysis. Psychoneuroendocrinology. 86: 152–168, 2017.