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.

Vicious Cycle – Aging and Declining Blood Sugar Control

Individual controls aging, , , , ,

Blog 18 – Age changes make it difficult to control blood sugar within a normal range.  Persistently high sugar levels create many problems.  The most significant is an acceleration of  aging that further promotes poor blood sugar control and hence high blood sugar. 

Hence, a vicious cycle is created that leads to preliminary stages of diabetes.  The origins of this cycle and effective means to disrupt it are presented in this blog and the next.

Introduction

Type 2 Diabetes (T2D) is the 7th leading cause of death in the elderly.  It is an insidious disease because there are no obvious early warning symptoms.  Moreover, T2D accelerates normal aging, increases the risk for heart disease and damages small blood vessels in multiple organs causing blindness, gangrene, reduced kidney function, impotence and neuropathy.  Fortunately, it is a potentially avoidable disease.

Prevention of T2D begins with assessment of fasting levels of blood sugar (clinically termed glucose).  A glucose concentration equal to or greater than 110 mg/100 ml of plasma after a 12-15 hour fast, obtained from repeat testing over 12 months, indicates an early but highly reversible stage of diabetes, termed prediabetes.  Other tests, HbA1c and glucose tolerance test (see Table 1 for details) are required to complement the fasting glucose values and could indicate progression to T2D.

Based on the most recent estimates by the CDC (2019), 26.4 million individuals over 65 have prediabetes based on results from one or more tests noted above.  However, this is an underestimation since many elderly avoid testing and thus remain uninformed on their risk for T2D.  

With a diagnosis of prediabetes, clinicians advise diet modification, weight loss and exercise (https://www.cdc.gov/diabetes/data/statistics-report/index.html).  While these strategies are effective if strictly followed, it is equally important for the elderly to understand the underlying reasons for the prediabetes in the first place and to have the option to minimize them.

The Influence of Aging on Blood Sugar Control

T2D is an age-related disease because aging influences blood sugar in two significant ways. 

    *One major age-related change is the well-documented decline in skeletal muscle mass. 

    *The second major change is the more recently documented age-related increase in the stress  hormone, cortisol.  Specifically, both resting and activated levels of cortisol increase with age and the response to stress is prolonged. 

Together, these age-allied modifications promote and sustain higher than normal levels of blood glucose, and thus create the prediabetic state.  Additionally, persistently high levels of glucose accelerate the deteriorative effects of aging, further disrupting glucose regulation.

Factor 1 – Age-Related Decline in Skeletal Muscle Mass

Several hormones and associated factors regulate blood glucose.  The most significant and most studied is insulin, a pancreatic hormone.  Following ingestion of food, metabolic processes liberate breakdown products such as glucose, amino acids and fatty acids into the blood.  Insulin, whose secretion is stimulated by rising glucose levels, facilitates the movement of these energy-rich nutrients especially glucose into the skeletal muscles for immediate use and into the fat and liver for storage. 

The problem for the elderly is this.  Skeletal muscle mass, comprising a significant portion (~40%) of total body mass, slowly declines with age.  It is the biggest consumer of available glucose whose delivery is assured by insulin.  However, if food consumption remains constant with age as it usually does, the same amount of glucose is still available BUT the end user e.g. the skeletal muscles, are reduced in size so less glucose is taken up.  Therefore, more glucose remains in the circulation and eventually is stored in the liver and fat.

The point is that with loss of muscle mass, circulating glucose remains higher for longer periods of time, supporting a prediabetic state.

Minimize Muscle Loss with Progressive Resistance Exercise

To keep blood glucose normal, muscle mass must remain constant.  Sadly, the loss of muscle mass with age is not obvious to most elderly.  This is because disappearing muscle tissue is replaced with fat deposits.  The only noticeable changes are a decline in muscle strength and associated unsteady balance.  A wealth of clinical trial data indicates that a program of progressive resistance exercise slows loss of muscle mass (and strength too).  It also improves insulin function called insulin sensitivity.  Insight 3, Progressive Resistance Exercise and Protein Supplements details these programs which may include free weights, resistance bands, weight machines and/or calisthenics.

An important corollary to a program of progressive resistance exercise is the recommendation to increase consumption of  proteins.  The building blocks of proteins are amino acids.  Amino acids stimulate muscle formation and are also incorporated into essential muscle proteins.  Quality proteins such as whey, soy and casein contain these amino acids. 

According to the government’s Recommended Daily Allowance (RDA), adults need to consume 56 grams of  protein each day to maintain general health.  In contrast, biogerontologists whose focus is the health span of the elderly, found the RDA to be inadequate for the elderly.  Consequently, the new, science-based recommendation for the elderly is twice the RDA.  To optimize muscle size and function, it is reasonable to consume quality proteins (whey, soy, casein containing essential amino acids) with meals and about 2 hours after a workout of resistance exercises.

Two Opposing Sides to Glucose

Glucose is an excellent source of energy for all cells in the body.  In contrast, it has a destructive side.  Glucose is a notorious oxidizer.  This means that glucose has the potential to  indiscriminately attack and damage nearby proteins, fats and DNA in tissues and cells.  Such oxidative modifications, if not repaired, contribute to reduced function and inflammation, hallmarks of aging.  Oxidative damage across the board makes it infinitely harder to keep glucose within an acceptable physiological range.

Vicious Cycle

Conclusions

It is incredibly important to maintain adequate control of  blood glucose.  In particular, glucose needs to be around long enough to provide a ready supply of energy to our muscles, but not long enough to exert oxidative damage.  Unfortunately, glucose is higher from longer periods of time in the elderly. This is because the muscles, the major consumer of glucose, diminish in size with age.  A program of progressive resistance exercise maintains muscle mass. However, absent this strategy, there is a risk of oxidative destruction to tissues and cells and a platform for prediabetes.

The second obstacle to  control of normal blood sugar is the age-related change in the stress response.  This is the topic of my next blog.

Table 1 – Tests Assessing Blood Sugar Control

TestMeasurementAbnormal Glucose Control  
Fasting GlucoseConcentration of glucose in the blood after
12-15 hour fast		 Equal to or greater than
110 milligrams/100 ml
HbA1cOxidation (glycation) of hemoglobin Equal to or greater than 5.7%
Glucose Tolerance TestGlucose levels following ingestion of 1 gram sugar/kg body wt. Glucose peak >140 mg/100 ml;
4-6 hours to return to near baseline
Select References:

Duchowny K et al., Muscle Weakness and Physical Disability in Older Americans: Longitudinal Findings from the U.S. Health and Retirement Study. Nutr Health Aging.  22(4): 501–507, 2018.

Gomes MJ et al., Skeletal muscle aging: influence of oxidative stress and physical exercise. Oncotarget 8: 20428-20440, 2017.  

Paddon-Jones, Rasmussen BB. Dietary protein recommendations and the prevention of sarcopenia.  Curr Opin Clin Nutr Metab Care. 12(1):  86–90, 2009.

Yau JW, Thor SM, Ramadas A. Nutritional Strategies in Prediabetes: A Scoping Review of Recent Evidence. Nutrients  12:  2990, 2020.

Zand A, Ibrhim K, Patham B. Prediabetes: Why Should We Care?  Methodist Debakey Cardiovasc J. 14 (4):  289-297, 2018.

Is Growth Hormone Really an Anti-Aging Supplement?

Individual controls aging, , , ,

Insight 17 – Despite considerable evidence to the contrary, human growth hormone maintains a reputation as a valid anti-aging therapy.  There exists a wealth of over-the-counter supplements claiming to elevate growth hormone levels and restore youthful vigor.  Unfortunately, claims of rejuvenation are exaggerated and associated adverse effects are played down.  This blog will discuss these issues and define alternative ways to stay healthy without human growth hormone supplements. 

Introduction

Growth hormone is one of many hormones produced by the pituitary gland, a small endocrine organ located at the base of the brain.  As aptly named, growth hormone plays a major role in the growth of an individual from birth to puberty and young adulthood.  However, growth hormone cannot take all the credit for influencing our growth.  It stimulates production of a liver hormone, insulin growth factor-1 (IGF-1), and the two partner together to exert biological influence. 

Changes in Growth Hormone with Age

Blood levels of growth hormone peak at puberty and decline about 80% by age 55 (as does IGF-1).  Along a similar timeline, muscle and bone mass peak in young adulthood and slowly decline with age roughly correlating with a fall in circulating growth hormone.  Since growth hormone and IGF-1 are significant effectors of muscle and bone health and since their levels fall with age, scientists reasoned that restoration of growth hormone to youthful levels (by infusion or injection) would reverse age changes in muscles and bones.  Hence, growth hormone should provide the desired rejuvenation.

Can Growth Hormone Rejuvenate the Aging Body?

Using the newly available synthetic growth hormone, a small study of 21 men (61-81 years of age) measured lean body mass (roughly muscle mass), fat mass, skin thickness and bone density before and after 6 months of daily injection of growth hormone (Rudman et al., 1990).  In 12 elderly men receiving growth hormone, muscle mass (8.8%)  and  bone density (1.6 %) increased, skin thickness increased (7.1%) and fat mass decreased (14.4%) compared to controls.  In 1990, these remarkable and significant findings supported the concept that growth hormone had rejuvenating powers.

The Negative Side of Growth Hormone

Sadly, this study and related hype raised appropriate skepticism.  Firstly, the study by Rudman et al., (1990) was too small for fundamental generalizations.  Additionally, treatment-associated negative effects such as an elevation in systolic blood pressure and fasting glucose levels in those receiving growth hormone, took a back seat.  Secondly, a review of 18 clinical trials (Liu et al., 2007) with growth hormone injections in men for up to 27 weeks, confirmed the earlier findings but emphasized that the extent of changes in body composition was very modest.  

Importantly, the small positive changes were outweighed by serious adverse effects. These adverse effects included:  a)  soft tissue swelling (edema); b)  joint stiffness (arthralgias); c) carpal tunnel syndrome (nerve compression due to fluid retention causing hand and finger pain); d)  enlargement of male breasts (gynecomastia) and e)  impaired fasting glucose (risk factor for diabetes mellitus).

Thirdly, despite the increase in muscle mass, there was no comparable increase in muscle strength.  This is exceedingly important because age-related loss of muscle strength (not muscle mass) leads to loss of physical independence.  Therefore, despite youthful levels of growth hormone, the beneficial effects in the elderly are too minor to warrant multiple serious adverse effects with no gain in muscle strength. 

Can Growth Hormone Accelerate Aging?

There is a wealth of evidence gathered from animal studies that a deficiency of growth hormone, whether artificial (genetic manipulation) or natural (hereditary) slows many aspects of aging and increases longevity.  On the one hand, growth hormone deficient animals exhibit small size, delayed puberty and reduced fertility.  On the other hand, these animals live longer than controls with normal growth hormone levels.  This is because many anti-aging activities such as increased resistance to stress and decline in pro-inflammatory mediators are enhanced when growth hormone is scarce.  Together these activities and many more, support a longer lifespan with lower levels of growth hormone.   

Growth Hormone Effects (injection/infusion)

Genetic disorders of growth hormone deficiency in humans exhibit similar changes.  These individuals exhibit a resistance to major diseases and although they do not have exceptional longevity, it appears that they enjoy a longer health span.  Taken together these findings suggest that growth hormone therapy for the healthy elderly has a significant potential to accelerate age changes.

An Alternative Approach Without Growth Hormone

As noted above, growth hormone use does not make muscles stronger.  Therefore, as discussed in (Insight  3, Progressive Resistance Exercise) a proven way to increase muscle strength is engagement in a serious program of resistance exercise, e.g. hand held weights or machines.  A program of progressive resistance exercises of increasing difficulty at home or in the gym will maintain muscle strength.  Optimal muscle strength ensures continued independence. Specifically, this is independence to carry out daily activities e.g. shopping, walking, housework. This leads to a better quality of life.  Additionally, progressive resistance exercise preserves balance and prevents falls

The Marketing of Growth Hormone Supplements

Growth hormone medications exist in many forms, all approved by the FDA.  Physicians prescribe them to treat well-defined endocrine deficiencies, affecting patients of all ages.  In contrast, the healthy elderly rely on advertisements of growth hormone supplements.  Websites claim that supplements, called secretagogues, boost blood levels of growth hormone.  Secretagogues are mixtures of select amino acids. 

Thus far, only one company tested their proprietary secretagogue mixture in human trials (2 clinical trials; 16 volunteers each).  Growth hormone levels rose significantly after a single oral dose of their secretagogue.  This information is worthwhile but it is extremely limited. 

Firstly, consider there are no clinical data at all for the many growth hormone secretagogues on the market.  Secondly, the two small trials mentioned above require confirmation by a larger number of volunteers, preferably with different doses and longer duration of use (not just 2 hours).  Thirdly, there are no data on the assumed positive effects of these supplements on energy output, muscle repair, and anti-aging potential.  Furthermore, there are no data on the negative adverse effects of these supplements.  

As stated above and reviewed by others (Bartke et al., 2021;Colon et al., 2019), the adverse effects of clinically tested growth hormone injections in the elderly outweigh the small effects on muscle, bone and fat mass.  Until evidence exists to the contrary, secretagogues that raise levels of growth hormone are expected to exhibit the same results.  Until more thorough trials are done, the best way to improve muscle mass and strength and decrease fat mass is with resistance and aerobic exercises.

Summary

Growth hormone fails as a hormone of rejuvenation.  In fact, extensive data in animals and some observations in humans suggest that growth hormone accelerates aging.  Clearly, for the healthy elderly, the multiple severe risks of growth hormone use far outweigh the small changes in muscle, bone and fat mass.  There is a safer way to build both muscle mass and strength.  It is an engagement in a progressive resistance exercise program either at home or at the gym. 

References (Complete reference list on request) articles on http://pubmed

Bartke A , Hascup E , Hascup K, Masternak MM. Growth Hormone and Aging: New Findings. World  J Mens Health. 39:   454-465, 2021

Liu et al., Systematic review: the safety and efficacy of growth hormone in the healthy elderly Ann Intern Med.146:  104-15, 2007.

Rudman D. et al., Effects of Human Growth Hormone in Men over 60 Years Old.  N Engl J Med. 323:  1-6, 1990.

How to Prevent Hearing Loss

Individual controls aging, , , , ,

Insight 16

Age-related hearing loss (ARHL) affects the majority of elderly individuals.  It is an insidious change that fosters reduced social interactions and isolation.  Studies now show that it is a significant risk factor for dementia.

Importantly, ARHL  is an age change that is mostly PREVENTABLE.  It is largely due to chronic or repeated exposure to loud noises throughout the lifespan.  Hearing aids are the standard treatment.  Unfortunately, they provide only a very minor improvement in hearing.  However, novel treatments with greater efficacy are on the horizon.

Background

We have a wealth of sensory organs that enable us to navigate our environment.  These organs provide perceptions of sight, sound, smell, taste, position in space, pain, temperature (hot/cold), touch, pressure, and vibration.  Although they are all important and are negatively affected to different extents by age, this blog is about the loss of sound perception. Importantly, this loss can be chiefly prevented.

From sound to speech perception

Speech perception is all about accurate processing of sound waves by the ear.

The ear converts mechanical waves in the air (sound) to electrical activity in the brain (speech perception).  The ear contains three chambers: a) outer, b) middle and c) inner.  The first two chambers maximize the mechanical waves and the inner chamber, called the cochlea, adds more sophistication and conversion to electrical activity.  Fibers of the auditory nerve relay electrical activity to the speech-specific region of the brain.

Age changes in the ear

ARHL results from deteriorative changes in the cochlea.  This sensory organ contains specialized cells called hair cells that exquisitely sense the frequency and amplitude of sound waves and relay them accurately via nerve fibers to the brain as understandable speech.  Within this system, there are two fairly well characterized age changes that distort speech  perception. 

The first well defined age change is the  disappearance or dysfunction of the hair cells.  The second, more recently identified age change, is the inability of nerve fibers to receive information from the hair cells.  The hair cells and the nerve fibers no longer communicate as expected.

Consequences of ARHL

Age changes result in altered speech perception.  Specifically, weak sounds are not amplified, strong sounds are not dampened and the specific frequencies associated with vowel and consonant sounds are passed to the brain in a blur.  In particular, there is a preferential reduction in processing of high frequencies used by consonant sounds (ch, th, sh, z). Speech comprehension becomes a challenge.  Loss of specific hair cells produces this change.

Another very disturbing change is the inability to hear in a noisy environment.  The ability to enhance local sound  (speaking to neighbors) and to dampen surrounding environmental noise (crowded room) is lost.  Loss of connections to the auditory nerve fibers produces this change.

Prevention of ARHL – Noise Avoidance

Avoidance of repeated or chronic exposure to loud noises largely prevents ARHL.  Sources of loud noises are many.  According to the CDC (cdc.gov) avoidable noises belong to specific categories such as a) daily activities e.g. high volume music on personal listening devices, b) events e.g. concerts, restaurants, bars, sporting events, movie theaters, and c) tools e.g. power tools, lawnmowers, leaf blowers, sirens, firearms, firecrackers.

Avoidance of loud noises is the most effective means for prevention of ARHL.  When this is not possible, a common sense approach is to dampen the loudness by use of earplugs and earmuffs and reduce the volume on personal listening devices.

Current Therapies

Hearing aids are the mainstay for treatment of mild to moderate hearing loss.  Current hearing aids (referred to as digital) are technologically more advanced than the older hearing aids (referred to as analog).  Both types work by amplifying sound, although the newer hearing aids claim to provide better sound clarity and ability to hear in a noisy environment.  Sadly, these claims are not met and only a fraction of the elderly with hearing loss are satisfied with their hearing aids.  Consequently, many do not use them. 

Present day hearing aids do not replicate the sensory activities of the cochlea.  In this regard, It is puzzling to experts in the field why hearing aids are still so ineffective.  Firstly, they argue that scientists already understand essential components of hearing loss. Secondly, the technology such as quantum computers, nanotechnology and AI is available for application to hearing loss. Furthermore, combination of the two could produce a hearing aid that compensates for hearing loss in all aspects, not just amplification. 

Future Therapies

Several biological therapies to reverse ARHL are under investigation.  These therapies include cell replacement of missing or dysfunctional hair cells, gene therapy  and addition of nerve growth factors to the cochlea.  Although successful in animals, there therapies await evaluation in man.

Summary

Approximately 70% of elderly experience some degree of hearing loss.  Repeated exposure to loud noises is the prime cause of age-related hearing loss.  Sadly, the use of digital hearing aids, which primarily amplify sound, helps only a small percentage of elderly. However, future therapies, whether biological treatments or technologically advanced hearing aids are possible.  A worthwhile goal of the healthcare community is commitment and funding to develop the ideal hearing aid.

Write me to receive a list of references used for this blog.

Insight 15 – Why Biomarkers Are Better than Chronological Age

Individual controls aging, , , ,

Chronological Age verses Biological Age

There is no escaping the conclusion that age is the greatest risk factor for disease and death.  However, it is also apparent that age, i.e. chronological age (time from birth), is a poor indicator of the actual state of the aging process in our body.  In other words, chronological age does not accurately represent biological age. 

Chronological age, at best, provides an association with a population average of age-related changes.  This lack of individual sensitivity has bothered scientists from the early beginnings of research on aging (some 80 years ago).  Since chronological age fails to precisely define the extent of aging of an individual, there is a need for something better.  This something better is called a biomarker.  It is predicted that a validated biomarker or composite of biomarkers will replace chronological age in health reports in the future. Furthermore, insurance companies will rely on them to better evaluate appropriate therapy for the elderly. 

What Exactly is a Biomarker of Aging

Since chronological age can give only a very rough estimate of the aging process, scientists are seeking a measurement(s) that represents the summation of the age changes in an individual at a particular date.  This is termed a biomarker of aging.   A biomarker will indicate the extent of aging of all organ systems for each individual, and also define the risk of disease for that individual. 

Although finding the ideal biomarkers of aging is an incredibly challenging scientific endeavor, biomarkers of disease already exist and are routinely relied on to direct next steps in treatment.  A familiar example is the PSA (prostate-specific antigen), a substance (biomarker) produced by prostate tumors.  PSA levels give a measure of both tumor presence and efficacy of therapy.  Another example of a disease-related biomarker, albeit less well known, is ANP, atrial natriuretic peptide, levels of which increase in heart failure and subside as heart failure is managed.  Both of these biomarkers provided diagnostic and prognostic information that guides effective therapy.

Candidate Biomarkers of Aging

Biomarkers of aging are varied and range from measurements of physical fitness to molecular DNA changes.  Although there are hundreds of biomarkers of aging that are under serious evaluation, none has taken first place in acceptance by the scientific community.  Two measurements that could be useful candidates are 1) maximal aerobic capacity termed VO2max and 2) inflammatory mediators.  Both measurements have been used extensively to elucidate age changes in man.

a) Maximal aerobic capacity

VO2max requires the individual to exercise strenuously (treadmill or stationary bike) for a specified time period during which maximal effort, heart rate, blood pressure, and oxygen consumption are measured.  VO2max directly assesses the function of the heart, lungs, chest muscles, blood vessels and oxygen carrying capacity of the red blood cells.  Because it is a comprehensive test that accurately measures performance in critical organ systems, it has been used in clinical trials to measure biological age changes independent of chronological age.  Furthermore, test results from this measurement are predictive of future disease.

b) Inflammatory mediators

Scientists have identified many inflammatory mediators that could be valuable biomarkers of aging.  The most recognizable one, C-reactive protein, is now part of many blood sample tests.  Inflammatory mediators such as C-reactive protein are substances released with injury e.g. an open cut or wound, muscle pulls and strains, or blunt trauma.  Everyone is familiar with injury-related inflammation – the pain, redness, and swelling.  As uncomfortable as inflammation is, an adequate healing process requires this initial acute inflammatory state but importantly, only for a brief period.  In contrast, persistent inflammation following an injury leads to permanent, sometimes irreversible, tissue damage. 

During aging, some cells called senescent cells, change their looks and functions and randomly produce unwanted inflammatory mediators in the absence of an injury.  Senescent cells, unfortunately, support a state of chronic low grade inflammation termed inflammaging.  Consequently, inflammatory mediators would be important biomarkers of aging and are currently under intense investigation.

Why the Aging Process Needs Biomarkers

The aging process exerts widespread effects on the body.  It alters the structure and function of all components of our body, from molecules to organ systems.  Furthermore, these changes occur at different rates depending both on genes, the environment (mainly lifestyle choices) and their interaction (see Insight 1). The occurrence of age changes at different biological levels and at different rates produces an incredible heterogeneity (diversity) of aging among individuals.

Although the aging process is an unavoidable deteriorative process, an abundance of clinical data indicate that the appropriate selection of proven anti-aging programs lengthens the time in good health (expands the health span) and reduces the time spent in debilitation and disease (shortens the senescent span).  This is where biomarkers come in. 

The advantage of biomarkers lies in their ability to precisely determine the extent of biological aging at any one time.  This information is important for two reasons:

a)  it permits the individual to engage in the most relevant anti-aging program to retard aging and

b)  it provides individual  assessment of risk of future disease and disability, allowing an opportunity to reduce the risk.

Conclusions

The observation that chronological age fails to define biological aging, stimulates the continuing search for biomarkers of aging.  It is predicted that in the future biomarkers of aging will replace chronological age, precisely because biomarkers will accurately measure biological age changes in each individual, and additionally predict morbidity and mortality.  Furthermore, since the aging process is modifiable, accurate knowledge of the state of one’s aging provides the opportunity to engage in appropriate anti-aging programs that will promote longevity by extending the years of health.

Insight 14 – Computerized Brain Training – Good or Bad?

Brain aging, , , ,

One of the foremost concerns of elderly individuals is the possibility of cognitive decline or worse, dementia.  The awareness of the devastating mental losses wrought by Alzheimer’s Disease and other forms of dementia have created the urgency to find activities to prevent or slow cognitive decline.  One of many such activities is the use of computerized brain training exercises to achieve this goal.  This is the topic of my blog.

Background – Changes in Cognition with Age

Even in the absence of disease, some aspects of brain function such as information processing speed (basically the response speed to a mental stimulus), some types of memory such as encoding and retrieval, executive function (basically global decision making) and reward-based behavior tend to decline with age.  In contrast, functions such as semantic memory (facts/knowledge), most aspects of language, emotional processing, autobiographical memory (about self) and automatic memory processes  (rote memory such as riding a bike) remain unchanged with age but are affected by disease.  See (Insight 6 – More longevity building: Ways to minimize brain aging) for a more in depth discussion of aspects of cognition that change or remain stable and their consequences.

Several approaches to minimize age-associated cognitive decline have already gained convincing clinical support (reviewed in Insight 6 – More longevity building: Ways to minimize brain aging).  They are:  

a) a program of aerobic exercise (Insight 4: Anti-aging benefits of aerobic and stretch exercises)

b) continued engagement in serious mental stimulation

c) mastery of new skills

d) optimizing vision and hearing. 

The data indicate that commitment to these 4 pursuits maintains cognition and slows cognitive decline.  These pursuits work because they physically change the brain’s neural networks for the better.  This is termed neuroplasticity.  Thanks to this mechanism, our nerves and connections are strengthened.

Is it reasonable to engage in computerized brain training to prevent cognitive decline?

Computerized brain training

There are now hundreds of companies worldwide that sell computerized brain training exercises. These exercises are referred to as computerized cognitive training (CCT).  Another name for computerized brain training or CCT is computerized brain games. The idea behind CCT is that hours of repetitive practice on standardized exercises will improve the function of the exercise-targeted brain domain.  For example, cognitive training in processing speed should improve reaction time or cognitive training in memory for encoding and retrieval should produce better recall of a list of items.  This training could possibly translate into more global cognitive function and enhance every day activities called  instrumental activities of daily living, such as handling finances, shopping, meal preparation.  

There are three forms of cognitive intervention: cognitive training, cognitive stimulation, and cognitive rehabilitation (Gates et al., 2019).  Cognitive training serves to prevent cognitive decline.  In contrast, cognitive stimulation and rehabilitation restore reduced cognitive function, and compensate for cognitive impairment, respectively.  This blog will discuss the science of cognitive training only.

The efficacy of computerized brain training is unsettled.

Analysis of Computerized Brain Training

There exist hundreds of clinical trials that studied the merits of computerized brain training.  Many of these trials tested a small  number of participants which reduces confidence in the results.  Additionally, in some trials, control participants were “passive controls” who were not exposed to any type of computerized exercise, also reducing confidence in the results.  Considering these issues, it seemed reasonable to focus on critical reviews of the computerized brain training trials.  A review or summary of a large number of trials is called a systematic review. A statistical analysis of a select number of trials that meet strict criteria is called a meta-analysis.  Both review types provide important information.

Early Findings

One of the earliest reports on CCT was a systematic review by Kueider et al., (2012). The authors reviewed the top 38 studies (out of 115) covering the prior 25 years.  These select studies trained elderly (55 years and older) who were without mild cognitive impairment or dementia.  The training included CCT as well as neuropsychological software and video games.  The authors concluded that there were cognitive benefits regardless of the training venue and that “computerized training is effective”.  Use of CCTs produced higher scores in processing speed, memory, attention and executive function.

Several years later, in contrast, an extensive list of eminent professors of gerontology, psychology, neuroscience, neurology, cognitive sciences and related fields submitted a position paper on computerized cognitive training.  See (https://longevity.stanford.edu)for details.  “The strong consensus of this group is that the scientific literature does not support claims that the use of software-based “brain games” alters neural functioning in ways that improve general cognitive performance in everyday life, or prevent cognitive slowing and brain disease”.   That was in 2014.  Since then, several excellent reviews appeared.

Recent Findings

Efficacy supported by meta-analysis

Bonnechère et al., (2020) published a meta-analysis of clinical trials in which participants practiced with commercially available brain training exercises.  Specifically, the goal was to demonstrate maintenance of cognitive function in people, 60 years and older, without any known cognitive difficulties.  The analysis statistically assessed 16 studies which together totaled 1500 patients. Independent of the participants’ age and time devoted to training, the authors conclude that these commercially available exercises improve memory, executive function and processing speed with the greatest improvement in processing speed.  There was no improvement in attention or visuospatial skills.  

This is an interesting review in that it provides for each analyzed study, the name of the cognitive exercise, the company producing the exercise and examples of the “workings” of the exercise.  Unfortunately, some studies enrolled small numbers of participants with about a 10% or so drop-out rate to boot. Importantly, the relation to global function or instrumental activities of daily living was not studied.

Efficacy unsupported by meta-analysis

With a different view, Gates et al., (2019; 2020) reviewed nearly 8000 clinical trial reports (including quasi clinical trials, published and unpublished trials).  Their criteria accepted only trials of computerized cognitive training that lasted for 12 weeks of more, in individuals, 65 years and older with the goal of improvement in cognition of cognitively healthy elderly.  Eight randomized clinical trials with a total of 1183 participants met these criteria. 

Gates et al., (2019) concluded that outcomes of these trials were in the range of low to very low confidence. In short this means that more research is required before one can confidently conclude that computerized brain training improves cognition of cognitively healthy elderly.  This supports the 2014 conclusion of numerous experts in the field (see above).  Gates et al., (2019) also points out that there are no long term studies on cognitive brain exercises (beyond 12 weeks or so). Additionally, there is a paucity of data on the harmful effects (such as anxiety, frustration) of computerized brain exercises. 

Summary – Computerized brain training needs more research

Today, the development and sales of computerized cognitive training, stimulation and rehabilitation is a multi-billion dollar industry.  Findings of major critical reviews in the field of computerized cognitive training indicate that test scores increase with specific training in multiple brain domains.  Importantly, one gets a higher score with repetitive practice using computerized brain training.  Unfortunately, there is no data at present to confirm that spending hours on computerized brain exercises will translate into a more effective ability to carry out daily cognitive challenges.

Select References

Gates NJ, et al.,  Computerized cognitive training for maintaining cognitive function in

cognitively healthy people in late life.  Cochran Database Syst Rev.  13: 1-94, 2019

Kueider et al., Computerized Cognitive Training with Older Adults: A Systematic Review.  PLoS ONE 7:  2012 e40588

Bonnechère, B et al, The use of commercial computerised cognitive games in older adults: a meta‑analysis. Sci Rep. 2020 Sep 17;10(1):15276

Gates NJ et al., Computerized cognitive training for 12 or more weeks for maintaining cognitive function cognitively healthy in late life (review) Cochrane Database of Systematic Reviews 2020, Issue 2. Art. No.: CD012277.

Insight 13 – Microbiota, Health and Longevity

Individual controls aging, , ,

Humans owe a great deal to the wealth of microorganisms that reside within and on their bodies.  In fact, these microorganisms outnumber our own cells and if counting total number of genes, resident microbial genes equal human genes.  Thus, they are ever with us and in great numbers.  Their contribution to our health and aging is just being defined.  Our present understanding of the relation between aging and microorganisms, mostly bacteria, will be discussed in this blog.

Orientation

The 100 trillion microorganisms that share space with us are called the microbiota.  Most of them reside in our gastrointestinal (GI) tract from the esophagus to the colon but some are located on the skin and in the urogenital tract.  The GI microbiota (focus of the blog) are comprised mainly but not solely of bacteria.  Other microorganisms e.g. fungi, viruses, protozoan and archaea (bacteria-like organisms) are also present but unlike the bacteria, little is known about their contribution to our health.

In the newborn, the GI tract is colonized by maternal microorganisms in several ways:  before birth in utero, and during vaginal delivery or if cesarean delivery, from environmental sources.  Breast milk adds additional microorganisms to the GI tract.  Up to 3 years of age the microbiota is modest in size and function.  Thereafter, the microbiota is more firmly established and remains fairly stable throughout adulthood.  The primary, but not the only determinant of the diversity and quality of the microbiota, is the diet.  As one ages into the 70s and beyond, the microbiota becomes less robust for reasons, as yet, not adequately defined. 

Exceptional and Abundant Contributions of the GI Microbiota.

Our understanding of the GI bacterial microbiota has accelerated due to technological advances in genetics and molecular biology.  These techniques consist of high throughput DNA analysis of multiple communities of bacteria (metagenomices) and the products they produce (metabolomics). 

Beneficial bacteria contribute to our health by fulfilling the following functions: 

a)  Mediate and restrain  inflammatory processes, energy expenditure, fat deposition and satiety (feeling full);

b)  Influence numerous local activities:  GI motility (movement of food via GI muscle contraction); level of neurotransmitters, serotonin, dopamine and gamma-amino-butyric acid; aid in the maturation of the immune system; facilitate GI mucus production and replacement of defective cells to keep the GI lining intact;

c)  Suppress  “bad” bacteria  such as Clostridioides difficile and Salmonella;

d)  Produce several vitamins (B and K vitamins)

Microbiota contribute impressively to our health through these various functions. It is evident that loss of these functions creates a vulnerability to disease.

Composition of the Microbiota

Microbiota bacteria belong to one of four phyla: Bacteroidetes, Actinobacteria, Firmicutes and Proteobacteria.   Key points on each phyla are:

Bacteroidetes comprise 25% of the assessed bacteria and are generally beneficial.  They adapt to available nutrients, expel bacterial toxins and work effectively with the immune system. 

Actinobacteria include diverse members but one genus, the Bifidobacteria are stars.  They produce B-vitamins and folic acid, reduce liver toxins, act as immuno-regulators, lower cholesterol and triglycerides and suppress pathogens. 

Firmicutes function to metabolize carbohydrates and convert them into short chain fatty acids which are necessary for protection of the lining of the GI tract and exert anti-inflammatory actions.  However, some members of phyla when found in high concentrations, create a vulnerability to GI disorders and diseases.

Proteobacteria often represent a problem since they contains some well known pathogens e.g. Salmonella, and some strains of E. coli. 

Ideally, an optimal microbiota consists of an abundance of Bacteroidetes, Bifidobacteria and Firmicutes and low levels of Proteobacteria. 

Microbiota benefit us in multiple ways to optimize GI health; harmful bacteria are suppressed by “good” bacteria

Factors That Shape the Microbiota:  Diet and Aging

Diet: 

Many factors alter the overall makeup of the microbiota and contribute to the variability that exists from one individual to the next.  However, diet is of prime importance in influencing the microbiota composition.  In particular, a plant-based diet, high in fruits, vegetable and fiber establish a microbiota with an abundance of diverse beneficial bacteria.  Previous blogs (Insight 10, Insight 11) give examples of the components of a plant-based diets.  

Classic Study

A classic study compared the microbiota of African children to that of European children.  The former consume an agrarian diet high in fruits, vegetables, fiber and low in protein while European children consume a Western diet high in fats and low in fiber.  The microbiota of these two groups differed significantly.  Compared to the microbiota of the European children, the microbiota of African  children exhibited considerable more bacterial diversity and higher amounts of bacteria that digest carbohydrate, many of which did not exist in the microbiota of European children. They also exhibited reduced amounts of pathogens such as Shigella and Escherichia and greater abundances of short chain fatty acids produced by the microbiota and essential for optimal gut health.

Additional Dietary Studies

Many controlled dietary studies, albeit limited (small number of volunteers and of short duration) in adults support these early findings.  In 2020, Ghosh et al., reported the results of a yearlong clinical trial of over  600 individuals (65-79 years of age) across 5 countries eating a customized Mediterranean diet.  This study assessed the microbiota, markers of inflammation, frailty and cognitive function at baseline and after one year of consumption of the Mediterranean Diet.  This trial showed that adherence to the Mediterranean Diet produced an enrichment in bacterial groups that were associated with reduced inflammatory markers, reduced frailty and higher cognitive function.  Clearly, long term dietary patterns are effective in establishing changes associated with optimal health.

Aging:

As evidenced by the results of the aforementioned clinical trial, dietary patterns greatly influence the microbiota after the 7th decade. Unfortunately, compared to younger individuals, the microbiota of many elderly exhibit reduced bacterial diversity.  This loss of diversity has been related, in part, to changes in dietary selections influenced by age-related changes in dentition (teeth), smell and taste, and medication use.  The microbiota of elderly in long term care facilities is especially deficient in beneficial bacteria and  even lack the ability to recover from antibiotic therapy as is generally the case for community dwelling elderly. 

Whether a loss of diversity in the microbiota contributes to age-associated conditions such as diabetes, cardiovascular disease, cancers and cognitive impairment is the focus of a plethora of current studies.  As with Ghosh et al., the data suggest an association between the microbiota composition and disease states.  Whether this is just a statistical association or a causal effect is unknown at present.

Strategies to Alter the Gut Microbiota

There are several potential strategies to optimize the microbiota.  Based on the aforementioned discussion, it seems reasonable for one to attempt to achieve the greatest diversity in bacterial phyla. This provides the benefits of the many unique bacterial functions e.g. vitamin and short chain fatty acid production, enhanced immune function and suppression of pathogenic bacteria.  Another goal is to avoid GI disorders such as any number of inflammatory bowel diseases.

Possible Strategies Are: 

a) Diet

As indicated above, diet exerts a significant influence on the microbiota.  Since most individuals in the USA do not consume a Mediterranean Diet, adding select substances to the diet has received considerable investigative attention.  This necessitates the addition of prebiotics which are non-digestible oligosaccharides (NDOs, actually long chains of sugars making a type of carbohydrate), and soluble fermentable fibers to the diet.  Plants, such as soybeans, legumes, onions, Jerusalem artichokes, and chicory are NDOs and soluble fermentable fibers include foods such as sauerkraut or kimchi.  At present, the effectiveness of prebiotics is equivocal with some trials showing microbiota improvement and others not.

b) Probiotics

Probiotics, defined  by the numerous health and food institutes (e.g.  Health Canada, the World Gastroenterology Organization, the European Food Safety Authority, Institute of Food Technologists) are “live microorganisms that, when administered in adequate amounts, confer a health benefit on the host”.   These live microorganisms, generally include strains of Lactobacilli, Bifidobacteria and Saccharomycetes.  Currently, some brands of yogurt, fermented foods (e.g. sauerkraut) and dietary supplements contain probiotics.  Despite extensive marketing and some positive clinical trial results, the FDA has not as yet given approval for probiotics.

c) Fecal Microbiota Transplants

This is transfer of fecal material from one person to another.  Approved by FDA, this is an effective therapy for Clostridioides difficile (C. difficile) infection and inflammatory bowel diseases.

Summary

An enormous entourage of diverse bacteria inhabit our GI tract.  Most are beneficial, assisting us in numerous ways.  Scientists are keen to understand in more detail, how these bacterial colonies keep us healthy, suppress pathogens and possibly contribute to our longevity.  Future studies will define the relation between aging and the microbiota. Specifically, future studies will determine whether the aging GI tract adversely harms the microbiota and whether lack of maintenance of the microbiota by poor life style choices causes GI aging and disease. It is essential to have clear answers to both of these issues.

A PDF of references for this blog is available on request.

Insight 12 -Ways to forestall aging of the skin

Individual controls aging, Skin aging, , , , ,

Introduction

Despite the growing number of individuals joining the ranks of senior citizens, our culture remains focused on its youth and hence, there exists the pressure to stay young as long as possible.  The desire to preserve a youthful appearance is encouraged by the development of an abundance of cosmetics, creams, lotions, injections, chemical processes and surgical procedures to prevent, minimize or remove wrinkles, sags and fine lines.  These treatments are effective but undoubtedly expensive.  At the top of the list is the surgical face lift that lasts years, then injections of fillers of collagen or matrix-derived compounds needed every 8 months or so, and Botox injections that relax skeletal muscles and last several months.

However, understanding the science of aging skin allows one to sidestep these costly treatments and to minimize wrinkles, sags and fine lines with the least expense possible.  The two least expensive effective products to use are:  broad spectrum sunscreens and the retinoids.  Since 70% of age changes are controlled by the individual (see Insight 1), use of these products allows individual control.

Additionally, in reducing wrinkles and sags, many more important benefits occur. These benefits are:

(1)  reduced risk of skin cancers

(2)  improved skin blood flow assuring health of the skin and

(3)  retention of resident immune cells as first line of defense against infections. 

This blog will elucidate the essential knowledge on aging skin so as to achieve these essential benefits.

Verified age changes in the skin

Extrinsic/Intrinsic Aging

There are two types of aging processes that affect the skin:  extrinsic and intrinsic.  The former results from chronic exposure to externally generated irritants such as ultraviolet radiation (UVR), extreme temperatures and pollutants.  Extrinsic aging, commonly called photoaging, harms the exposed (unclothed) skin of the face, neck, arms, and legs.  Extrinsic factors rapidly accelerate the aging process and establish irreversible changes.

In contrast, intrinsic aging, also called normal aging, occurs very slowly as a result of internal changes such as nutrient availability, inflammatory damage and oxidative events.  Intrinsic aging occurs in areas that are usually covered by clothing or are hidden (such as the chest and back, buttock, underarms and behind the ears).  External factors have little effect on protected areas.  

There are three distinct layers to the skin : epidermis (top), dermis (middle) and hypodermis (bottom).  Because each layer contains different cells and relevant support material, each layer ages differently.  Since the focus of this blog is to discuss how to minimize wrinkles, sags and fine lines, only extrinsic aging which is the main cause of wrinkles, sags and fine lines,  will be detailed.

Wrinkles, sags, fine lines

Facial wrinkles develop mainly through external damage from solar ultraviolet radiation (UVR).  UVR consists of 3 different wave components:  UVA, UVB and UVC.  UVC is of no consequence as it does not enter the atmosphere.  UVA and UVB penetrate the atmosphere and injure human skin.

Epidermis of the skin

UVB penetrates the epidermis, the top layer of the skin but no more.  Too much UVB causes a sunburn.  Chronic UVB exposure irritates resident cells of the epidermis, called epithelial cells, and eventually induces a unnatural thickening of this outer layer. 

Dermis of the skin

Unlike UVB, UVA is insidious since it does not produce overt effects such as sunburn.  UVA penetrates down to the second layer of the skin, the dermis and damages the fibroblasts, the cells tasked with housekeeping duties of the dermis.  Fibroblasts traumatized by UVA progress to a terminal stage loosely termed senescent cells or scientifically termed, the senescent-associated secretory phenotype (SASP). 

SASP cells become tragic residents of the dermis because they are dramatically and permanently altered to cause chronic damage to the dermis.  These converted cells are notoriously harmful because:

(1)  the SASP is unable to divide and hence cannot renew itself, an effective way to eliminate oxidized compounds,

(2)  SASP aberrant function replaces normal fibroblast function. Consequently, the SASP produces an abundance of unwanted inflammatory mediators and harmful enzymes .  These substances destroy the support platform of the dermis.   

(3)  despite the harmful effects of the SASP, this cell type persists.  It is immune to cellular mechanisms to destroy it.

Consequently, these changes allow for gravity to overcome the  deteriorating weakened structure of the dermis to produce wrinkles and sags.  UVA-induction of the SASP is central to wrinkles and sags. 

Hypodermis of the skin

The hypodermis is the fatty layer under the dermis.  It, too, is affected by external damage from UVA.  Combined with normal aging, the hypodermis decreases in thickness.  Additionally, the matrix supporting the fat cells deteriorates and fat cells lose functionality, size and adherence to the dermal layer.  Thus another layer of support is modified in favor of wrinkles and sags.

Therefore, UVR-induced changes in the epidermis, dermis and hypodermis reduce the mechanical strength of the facial skin and other exposed skin and allow the forces of gravity to exert their effects, creating wrinkles and sags.  This is mainly brought about with chronic exposure to UVA.

Prevention of wrinkles and sags

Broad Spectrum Sunscreens

Since UVR is the major instigator of facial wrinkles and sags, blocking UVR with a sunscreen is a reasonable solution.  However, it was not until 2012 that the FDA approved the addition of UVA-blocking compounds in sunscreens.  Prior to this date, sunscreen only contained UVB-blocking substances to prevent sunburns. 

UVB blockers were termed sun protection factors (SPFs) and sunscreens were labeled according to the blocking strength of the UVB compound.  SPF ranges in strength from 15 to 75 or more.  With the realization that UVA, not UVB, causes skin cancers and facial aging, approval was granted to add UVA-blocking compounds to sunscreens.  Hurrah!!  Sunscreens with these compounds and UVB-blockers are now called broad spectrum sunscreens with SPF.  If used correctly (according to the directions), broad spectrum sunscreens will block both UVA and UVB radiation.  Chronic use of the broad spectrum sunscreens from a young age onward will significantly reduce wrinkles and sags. 

Two issues of importance: 

Firstly,  the compounds blocking UVA are of two types, ones that are absorbed and ones that are not.  Avobenzene belongs to the former; zinc oxide belongs to the latter.  So far both are considered safe but controversy has arisen regarding the safety of the absorbable anti-UVA compounds. 

Secondly, the chronic use of sunscreens limits the production of vitamin D in the skin.  If sunscreens are used constantly, this source of  vitamin D is inhibited and additional sources of vitamin D, e.g.  foods fortified with vitamin D or from supplements, are required.

Retinoids

Since protection against UVA was not available until 2012, most elderly today received generous amounts of UVA that caused facial wrinkles and sags.  To ameliorate this, the family of retinoids (retinol, retinaldehyde, retinoic acid also known as tretinoin), are beneficial.  Retinoids are essentially different forms of vitamin A.  When applied to the skin, retinoids reduce the photoaging effects of UVA.  In a number of small clinical trials, topical application of these compounds reversed or minimized age-associated facial lines, and wrinkles. 

It is known that retinoids activate epidermal and dermal cells with the result of enhancement of cell renewal, increased blood flow and maintenance of the dermal structure. Hence, retinoids reverse the damaging effects of UVA. 

The single major adverse effect with use of  retinoids is skin irritation or rash.  The mechanism for this is unknown and under investigation.   

Conclusions

Chronic external damage (mainly UVA) to a large portion of the skin causes wrinkles, sags and fine lines.  These are changes with serious psychological effects.  Importantly, underlying this is reduced physiological function of the skin that gives rise to skin cancers, poor wound healing and decreased defense against bacterial infections.

Use of broad spectrum sunscreens and retinoids protects the skin against extrinsic age changes. This assures many excellent benefits ranging from reduction in wrinkles and sags to optimal wound healing and decreased risk of skin cancers.

Insight 11 -Okinawa, DASH and Portfolio Diets

Individual controls aging, , ,

Diet to extend the health span

Innumerable scientific studies show that adherence to the Mediterranean Diet reduces deaths due to cardiovascular disease and therefore, increases the lifespan (see Insight 10).  As discussed below, several other diets, Okinawa, DASH, and Portfolio, reduce risk factors for cardiovascular disease. 

1.  Okinawa Diet

Background

Okinawa is a Japanese island where life expectancy since the end of WWII has been the highest in the world.  Although Okinawan life expectancy today is no longer higher than the Japanese national average, nevertheless, life expectancy in Japan relative to other countries remains exceptionally high.  As proof, Japan’s life expectancy ranks second among 191 countries  (average of both genders, 85 years in 2020  (www.worldometers.info/demographics/life-expectancy/). By comparison, life expectancy in the USA ranks 46 among 191 countries.

Okinawa Dietary Components

The Okinawa diet is the main factor contributing to the longevity of Okinawans and the plethora of centenarians.  The Okinawa diet is a plant-based diet that is high in consumption of vegetables and thus low in calories. Although low in calories, the diet is nutritionally dense with an abundance of vitamins and compounds with antioxidative effects.  Interestingly, the preferred vegetable, the sweet potato, is one with a low glycemic index, meaning it is metabolized slowly thus avoiding high surges in blood sugar that predisposes one to pre-diabetes and subsequent Type 2 Diabetes.  The diet includes moderate consumption of proteins and a selection of mono/polyunsaturated fatty acids in place of saturated fats.  Diet details are summarized below.  

Okinawa Diet Benefits

Clearly, the traditional Okinawa Diet as practiced by residents of Okinawa effectively forestalls the onset of age-associated diseases and increases the lifespan.  As discussed earlier (Insight 8), lifelong caloric restriction in many animal models from round worm to monkey, not only dramatically extends the maximal lifespan but reduces inflammation,  improves insulin sensitivity, and delays onset of diseases.  The Okinawa Diet is low in calories so it may provide benefits simply through reduction in calories. 

Additionally, the Okinawa diet is low in protein and high in low glycemic carbohydrates.  When mice are maintained on a diet comparable to the Okinawa Diet, their life span increases significantly.   Human dietary studies are difficult to perform but generally low protein consumption is not associated with a decrease in mortality.  On the contrary, diets high in protein and low in carbohydrates (opposite to the Okinawa Diet) are associated with increased mortality.  More data are needed to understand the role of protein in aging. 

Freshly dug sweet potatoes

2.  DASH Diet

Background

The DASH diet was developed more than 20 years ago to reduced the prevalence of hypertension.  DASH is an acronym for Dietary Approach to Stop Hypertension.  The prevalence of hypertension increases with age.  The prevalence in adults is ~ 30%, in those 65-80 years ~58% and as high as ~74% in those over 80 years of age.  Furthermore, elevated blood pressure predisposes one to cardiovascular diseases such as atherosclerosis, stroke and heart failure.

DASH Dietary Components

Previous science indicates that certain foods could possibly lower blood pressure better than other foods.  This became the basis of the DASH diet. This diet recommends consumption of fruits and vegetables, whole grains, low-fat dairy products, beans, nuts and seeds and some fish and poultry.  Also consumption of saturated and trans fatty acids and cholesterol is reduced.  This diet is rich in nutrients such as potassium, magnesium, calcium, and fiber and lower in sodium compared to a Western Diet.

The Mayo Clinic has put together 3 days of meals that follow the DASH dietary plan.  Also included is the nutritional analysis of the foods for the 3 days.  It is worth checking out.  https://www.mayoclinic.org/healthy-lifestyle/nutrition-and-healthy-eating/in-depth/dash-diet/art-20047110

DASH Benefits

Numerous clinical trials show that the DASH Diet lowers both systolic (high number) and diastolic (lower number) blood pressure with greater reduction of blood pressure in those with higher baseline values.  Reducing sodium in the DASH Diet below the recommended amount produced an even greater reduction in blood pressure.

3.  Portfolio Diet

Background

This diet was developed to lower cholesterol and to prevent/reduce the onset of coronary artery disease. It was designed with scientific information that suggested certain foods (such as plant proteins and sterols, viscous fibers, nuts)  in various ways were helpful in reducing cholesterol.  High blood levels of LDL (bad cholesterol) is a serious risk factor for cardiovascular disease.

Portfolio Diet Components

The Portfolio Diet is basically a vegetarian diet.  It is rich in vegetables such as broccoli, eggplant, tomatoes, onions, okra, high in whole grains including oats and barley, and vegetable-based margarine, almonds, and soy protein. Soy products replace animal products and the accompanying saturated fat.  It is also low in sodium,  sweets, and refined carbohydrates.

WebMD has published a plan for what the typical Portfolio Diet would look like in daily life.  This is worth reading.  https://www.webmd.com/cholesterol-management/features/portfolio-diet-lower-cholesterol

Portfolio Diet Benefits

A systematic and meta-analysis in 2018 of the Portfolio diet in clinical trials longer than 3 weeks showed many benefits.  Benefits were reduction in LDL cholesterol, decrease in systolic/diastolic blood pressure, reduction in inflammatory factors and decreased risk of coronary heart disease.

Conclusions:

Whether you follow the diets discussed here or the Mediterranean Diet discussed earlier (Insight 10), there is ample evidence that inherence to these diets will result in longer healthier life.  Of the four diets, the scientific support for the Mediterranean Diet is the most extensive, but quality data also exists for the other three.

It is clear that all 4 diets differ radically from the typical Western diet.  The Western Diet is high in calories, saturated fats, meat and meat products, processed foods and sugar-laden foods. Consumption of fruits, vegetables and fiber is low.  Furthermore, the Western Diet is associated with development of obesity and cardiovascular disease.

Insight-11-referencesDownload

Insight 10-Best Longevity diet = Mediterranean Diet

Diet, Individual controls aging,

Best diet for longevity

I previously discussed in Insight 8 that severe caloric restriction retards the onset of many diseases and increases longevity in animal models of aging (including the monkey).  I subsequently presented the status of the future caloric-mimetic drugs. These drugs are predicted to offer the same benefits (health and longevity) of caloric restriction minus the pain of caloric restriction (Insight 9).  However, in the interim until the advent of efficacious caloric-mimetic drugs, the question remains as to what is the best diet for longevity building.  The best answer to date is the Mediterranean diet.  It is the diet with the most convincing scientific support.  Most importantly, adherence to this diet is associated with a decrease in the incidence of cardiovascular disease, the major cause of death in our society.  As a result, disease reduction indirectly increases lifespan.  

Components of the Mediterranean Diet

The Mediterranean diet entails consumption of whole grains, legumes, fruits, vegetables, nuts, fish and olive oil, wine in moderation, and a low-moderate intake of meat, dairy products, processed foods and sweets (Vitale et al., 2018).  This ~2000 calorie/day diet derives more calories from plant based foods than from meat based foods and fat consumption is largely from mono- and polyunsaturated fats.  More details are presented in the adjacent table.  This table is the result of an extensive systemic review (59 studies) of the health effects of the Mediterranean diet (D’Alessandro et al., 2019).  The authors were able to assess the effect of each food group on disease prevention. From that, they developed the frequency and serving size of the components of this diet needed to achieve these health benefits.      

Summarized from D’Alessandro et al., 2019

Origin of the Mediterranean diet

A study called Seven Countries Study of Cardiovascular Diseases began in the late 1950s and continued for some 50 years.  This seminal study tracked over 12,000 middle-aged men in North America, Northern Europe, and Southern Europe. It correlated dietary patterns with the incidence and mortality rates for coronary heart disease (CHD) and overall mortality (Menotti  and Puddu, 2015).  The striking findings showed that the incidence of CHD, other cardiovascular diseases and overall mortality was lower in southern Europe (Mediterranean countries and Japan) than anywhere else.  This improved health and longevity significantly correlated with decreased saturated fat consumption (low levels of serum cholesterol) and increased calorie intake from plant foods relative to animal meats.  In other words, this became known as the Mediterranean diet.

Proven benefits of the Mediterranean diet

There are numerous observational studies and clinical trials on the effects of adherence to the Mediterranean diet to health outcomes.  To make sense of the wealth of data, meta-analysis combines results from the  most rigorous studies to yield what are considered substantiated and valid conclusions.  The most recent of these meta analysis (Sofi et al., 2008; Dinu et al., 2018) evaluated 13 observational studies and 16 randomized clinical trials with regard to 37 different health outcomes. The results show adherence to the Mediterranean diet yields lower mortality for:

  1. Cardiovascular disease, Coronary heart disease, Heart attack
  2. Neurodegenerative diseases
  3. Cancers
  4. Diabetes
  5. All causes

However, there are limitations to studies assessing dietary patterns since they rely on validation of dietary questionnaires.  Hence, the need for the meta analysis that shows with a high degree of confidence that adherence to the Mediterranean diet compared to a non Mediterranean diet e.g. western diet, consistently yields valuable health benefits. 

Future – how the Mediterranean diet works

Several studies have endeavored to probe the underlying mechanism(s) of the Mediterranean diet on health benefits.  As a result, it has been shown, albeit in small studies, that the adherence to the Mediterranean diet for 6 months to one year lowers blood pressure (Davis et al., 2017; Jennings et al., 2019), improves dynamic blood flow (Davis et al., 2017), decreases proinflammatory mediators (Dyer et al., 2017) and reduces arterial stiffness (Jennings et al., 2019).

Other diets e.g. Okinawa, DASH and Portfolio will be discussed in my next blog.

ReferencesDownload