All posts by Glenda Bilder

About Glenda Bilder

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

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

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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

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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

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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

Insight 9 – Replacement for caloric restriction

Diet, Individual controls aging, , , , ,

The caloric restriction mimetic – better than starvation

Caloric restriction (CR) is severe reduction in calorie intake.  It must be maintained for an extended period of time and be supplemented with essential nutrients.  It is often called “starvation without malnutrition”.  However, the reward of this difficult protocol is exceptional:  a longer and healthier lifespan (see Insight 8).  The obvious problem is that, unlike animals under investigative experimentation, humans cannot endure this degree of starvation for any significant length of time.  Thus the search for drugs that would produce the same benefits of CR without the pain of eating less.  These drugs are termed caloric restriction mimetics (CRMs).

The caloric restriction mimetic – 3 of interest:

1.  Sirtuin (SIRT)-activating compounds e.g. resveratrol

2.  Metformin

3.  Rapamycin

Sirtuin-activating compounds

Sirtuin-activating compounds stimulate specific genes (SIRTs) to produce proteins termed sirtuins.  Sirtuins (chemically defined as NAD histone deacylases), in turn, act to change cell metabolism for the better.  Sirtuins perform several significant functions.  Some of these are 1) reduction of inflammation through depression of the master gene (NF-κβ), 2) greater recycling of damaged proteins, and  3) improvement of insulin signaling.  Together these activities and many more contribute to a healthier life.

How are sirtuins related to CR?  In animal models of aging, CR activates the genes (SIRT family) that produce the sirtuins and consequently, the level  of sirtuins increases with CR.  Secondly, in genetic experiments which insert an extra SIRT gene into an experimental animal, the level of sirtuins increases and beneficial changes comparable to CR occur.  So chemicals that elevate the level of sirtuins should produce the same beneficial effects of CR.  Thus the development of sirtuin-activating compounds.

Resveratrol – role in caloric restriction

A notable sirtuin-activating compound is resveratrol, originally isolated  from red wine and when concentrated (1000 fold), resveratrol produces effects similar to CR such as an increase in maximal lifespan, reduced inflammation, and delay in disease onset.   Unfortunately, resveratrol is poorly absorbed by the gastrointestinal tract and so analogs with greater bioavailability have been developed.  Analogues have been evaluated in rodents and in man.  Generally in rodents, improved health benefits e.g. delay in disease onset have been observed. 

In man, clinical trials assessing one particular analogue, SRT2104, for therapy of psoriasis, ulcerative colitis, sepsis, and vascular dysfunction in smokers and type 2 diabetes (T2D) have been completed.  Thus far only results for the effect of oral SRT2104 on psoriasis have been published and showed reasonable safety and a modest reduction of disease pathology.  This was a small study (40 patients, 84 days of treatment) that warrants additional evaluation according to Kreuger et al., (2015).   As published results become available, updates will be provided.

Metformin

Metformin is a caloric restriction mimetic.  It is also an FDA approved drug for treatment of T2D. Much is known on how it works to block production of glucose by the liver.  A striking finding was that patients taking metformin for T2D lived longer than those without diabetes and of course not taking metformin.

When used in animals, metformin delays the onset of disease and in some animal models of aging, it extends the lifespan.   It acts in multiple ways to alter nutrient sensing and improve cellular activities related to gene function, recycling of damaged cell components and slowing age-related changes.  These changes mirror those produced by lifelong CR. 

To further understand the caloric restriction mimetic effects of metformin, the FDA (2016) granted approval of its use in a clinical trial to determine whether metformin will delay the onset of disease.  The trial named Targeting Aging with Metformin (TAME) trial will enroll 3000 patients (65-79 years of age) and follow them for 6 years to determine whether metformin delays the onset of major age-related diseases e.g. heart disease, cancer and dementia (https://www.afar.org/tame-trial).  The results are eagerly awaited.

Rapamycin

Rapamycin is an antibiotic and potent immunosuppressant drug to prevent organ rejection.  In animal models of aging including the mouse, treatment with rapamycin extends the lifespan and delays the onset of age-related diseases.  Thus rapamycin is a caloric restriction mimetic.  It acts by inhibiting an important nutrient sensor called mTOR.  This nutrient sensor is activated by insulin.  Therefore, in the presence of rapamycin,  insulin-mediated metabolic effects are significantly reduced. 

Chronic use of rapamycin in man is limited to very low doses due to untoward side effects. However, the Dog Aging Project completed a placebo-controlled trial with 24 healthy companion dogs treated with a low dose of rapamycin for 10 weeks.  The drug is safe and improves cardiac function as determined by an echocardiogram before and after treatment.  Funded by a grant from National Institute of Aging and private donors, the next experiment will enroll a larger number of companion dogs and seek to determine whether aging can be delayed in dogs with this CRM.  

The objective of the Dog Aging Project (dogagingproject.org) is to understand aging in dogs and translate the information to humans.  This is based on observations that humans and dogs share the same environment, they have many biological mechanisms in common and also develop many of the same diseases.  Insights into dog aging should contribute to understanding human aging.

Comparison of diet and mimetics

Common Pathway

The schematic illustrates one known pathway altered by CRMs.  As with CR, these drugs also target the nutrient sensor termed mTOR (mammalian target of rapamycin).  This sensor was uncovered in part with studies using rapamycin.  mTOR is a key protein that affects many other essential pathways in the cell.  When its activity is reduced, more efficient metabolism ensues, recycling is enhanced and inflammation is minimized. The future caloric restriction mimetic will potentially replace dietary caloric restriction.

References of interest

1.  Krueger JG, Suarez-Farinas M, Cueto I et al.  A randomized, placebo-controlled study of SRT2104, s SIRT1 activator in patients with moderate to severe psoriasis. PLoS ONE 10(11): e0142081

2.  Kulkarni AS, Gubbi S, Barzilai N.  Benefits of metformin in attenuating the hallmarks of aging.  Cell Metab 32:  15-30, 2020.

3.  Urfer SR, Kaeberlein TL, Mailheau S.  A randomized controlled trial to establish effects of short-term rapamycin treatment in 24 middle aged companion dogs.  GeroScience 39:117–127, 2017.

Insight 8-Caloric Restriction

Diet, Individual controls aging, , , ,

Importance of caloric restriction (CR)

Previous blogs have focused on specific organ-systems such as skeletal muscle (Insights 2-5) and the brain (Insights 6,7).  Insight 8 describes a proven but difficult path to longevity that impacts ALL organ-systems. This path is one of rigorous caloric restriction. Thus caloric restriction promotes longevity. It is a longevity builder.

Low calorie foods

Not quite a century ago, a Cornell University researcher, Clive McKay who was studying nutrition in rats, reported that rats who ate 30% less calories than those with free access to food, appeared healthier and lived longer than the controls with unlimited access to food.  All rats consumed adequate intake of vitamins, minerals, essential amino acids and fats throughout the study.

Significance of caloric restriction

First, CR is a repeatable experiment. It has been replicated in many different animal models that include yeast, round worms, fruit flies, mice, dogs, and monkeys.  In all studies, CR restriction of 25-30 or more percent produces a significant extension of lifespan with positive effects on a variety of organ-systems.  

Secondly, the CR studies revealed at least one important mechanism of aging. Thus scientists now know that lifespan (at least from yeast to monkey) can be successfully lengthened with reduction in consumption of calories.

Thirdly, CR opened the door to the identification of drug “mimetics” of CR. These new drugs would work like CR but, importantly, bypass the known difficulty for humans to eat less.

Known benefits of caloric restriction

CR produces many benefits in addition to an increase in lifespan.  This has been studied in depth in rodents and monkeys.  Generally, compared to control animals, CR animals exhibit

   (a) a delay in the occurrence of major diseases,

   (b) a delay in the decline in muscle mass,

   (c) a delay in the decline of the immune system, and

   (d) a delay in the decline in some DNA repair mechanisms (protecting cells from random damage). 

Body temperature may decline slightly but overall physical activity in CR animals compared to controls is normal or slightly increased.  Significantly, and considered the driving force behind the above beneficial changes is a shift in how sugars are metabolized.  CR animals utilize new pathways that  reduce the requirement for insulin, a known pro-aging factor.

Results of CR in monkeys

One of the most important studies on CR are the ongoing ones using Rhesus monkeys at the National Institutes of Aging (NIA) and Wisconsin University (Colman et al., 2014; Mattison et al., 2017).  Monkeys began a 30 percent reduction in calories when they were adults.  After 20 years, the number of CR-treated monkeys exceeded that of the controls (survival in the CR group was 80% versus 50% in the control group).  Other benefits, to name a few, include:

   (a) a delay in age-related pathologies such as diabetes, cardiovascular disease, cancer and brain-related disorders;

   (b)  lower blood pressure, heart rate, fasting blood glucose and a favorable lipid profile (low LDL and triglycerides and high HDL);

   (c)  normal levels of testosterone and estrogen, maintenance of “youthful” levels of melatonin (sleep agent) and dihydroepiandrosterone (DHEA popular supplement considered the precursor to hormonal steroids such as estrogen and testosterone);

   (d) maintenance of immune system function (lower levels of inflammatory mediators and higher levels of anti-inflammatory agents); and

   (e) decreased oxidative damage to muscles and decreased onset of sarcopenia (see Insight 2). 

Application of caloric restriction to man

The first study in man was an observational, retrospective and case-controlled study of 18 volunteers (average age ~ 50 years) in self-imposed CR for 3-15 years paired with 18 healthy same age, sex, but eating a western diet (high fats and carbohydrates).  Compared to those eating the western diet, CR individuals had a lower body mass index, less body fat, more lean muscle mass, lower levels of LDL, triglycerides and fasting glucose and insulin and higher HDL and lower levels of a key inflammatory mediator, C-reactive protein (Fontana et al., 2004).

NIA sponsored the clinical trial, CALERIE = (Comprehensive Assessment of Long-term Effects of Reducing Intake of Energy) Study  which has completed several small (~50 volunteers) phase I trials of 6 months to 1 year duration and a larger (218 volunteers) phase II trial that lasted 2 years.  In both phases the target caloric reduction was a minimum of 25% but in phase I, individuals achieved a 10-17% caloric reduction and in the longer trial, only a 12% caloric reduction was achieved.  Even with this modest CR, there were positive changes such as decrease in fasting glucose, decrease in inflammatory makers, improved cell function and decrease in cardiovascular risk factors.  However, the CR reduction was too modest and phase II too short to achieve the milestones evident in the monkey studies.

Caloric restriction – next steps

The difficulty for humans to adhere to a 30% reduction in calories has ushered in interest in developing drugs to “mimic” CR.  As the thinking goes, in the future, individuals will be able to take a drug that mimics CR and also be able to eat whatever is desired.  Three candidate drugs have been proposed:

a) metformin

b) rapamycin

c) sirtuins

A discussion of these 3 compound will be the topic of my next blog.

References                          

Fontana et al.,  Proc Natl Acad Sci USA 101:  6659-63, 2004.

Colman et al., Nat Commun 5:  3557, 2014

Mattison et al., Nat Commun. 8:  14063, 2017.

Insight 7 – Brain Health and Sleep

Brain aging, Individual controls aging, , ,

Brain toxins and their disposal by the brain

One of the most exciting discoveries in the past decade is the identification of a “disposal” system in the brain that clears the brain of unwanted compounds (toxins), produced in the course of everyday living.  This system is termed the glymphatic system.  It shares a large portion of its name with a similar system that resides outside the brain.   This outside system is the immune lymphatic system  that protects us from viral and bacterial infections.

Characteristics of the glymphatics; importance of sleep

Unlike the immune lymphatic system, the glymphatic system resides solely in the brain and functions to clear proteins or parts of proteins that accumulate as byproducts of normal brain metabolism.  The main function of the glymphatics is to clear toxins.  Toxins filtered by the glymphatics in the brain are transported in small vessels down the neck and literally dumped into the immune lymphatic system for recycling or elimination elsewhere.  Thus the glymphatics contribute significantly to brain health and longevity!

Importantly, the glymphatic system only works at night.  It is associated with high frequency brain waves and low levels of norepinephrine, an essential brain regulator, that only occur during sleep.  Results of animal studies show that natural sleep produces the essential changes that facilitate the clearance of toxins, in particular beta amyloid protein, implicated in the development and progression of Alzheimer’s Disease.  Therefore, sleep appears to serve an extremely important function – enhancing the clearance of metabolic waste products.  As summarized by researchers at the Langone Medical Center, New York University “restorative function of sleep may be due to the switching of the brain into a functional state that facilitates the clearance of degradation products of neural activity that accumulate during wakefulness” (Xie, Kang, Xu et al., 2013).

The clearance of toxins by the glymphatic system applies to all neurotoxins.  It is postulated that reduced clearance of neurotoxins may contribute not only to the development of Alzheimer’s Disease but may influence the presence of several other diseases e.g. Parkinson’s Disease, Huntingdon’s Disease, amyotrophic lateral sclerosis and frontotemporal dementia.

Age-associated changes in sleep may retard toxin clearance

Age-associated Sleep Stages

Unfortunately sleep quality decrease with age.  Sleep physiology consists of 4 stages per each sleep cycle and the occurrence of about 8-9 cycles per night.  Different brain activities occur in each stage.  For example, stages 1 and 2 constitute light sleep while stages 3 and 4 comprise deep sleep and are followed by REM (rapid-eye movement) associated with dreaming.  Additionally, there is a period of quiet wakefulness prior to sleep. 

With age, the following changes occur:

(1) the period of quiet wakefulness increases such that it takes longer to fall asleep

(2) the time spent in stages 1 and 2 increases – increasing the number of awakenings referred to as sleep fragmentation

(3) the time spent in deep sleep (stages 3 an 4) decreases and may disappear – resulting in the feeling of “not rested”

These changes may lead to daytime “napping” and possibly progress to insomnia.  Many factors such as medication use, nocturnal urinary frequency, chronic pain, hormonal changes and age-related co-morbidities, exacerbate age-related changes in sleep patterns. 

It is important to know how age-related changes in sleep affect the function of the glymphatics.  Regrettably, this has not been critically studied in the elderly.  It is known that the extreme condition of no sleep, insomnia, shuts down the glymphatics, allowing build-up of neurological toxins. 

How to improve quality of sleep

There is no firm answer on how to improve sleep quality.  Clinical trials, generally small with 40-60 participants, point to two interventions that improve sleep quality in the elderly:  a program of aerobic exercise and cognitive behavior therapy (CBT).  Insight 4 provides sufficient detail for a meaningful program of aerobic exercise.   

CBT is a program that provides instruction on the essentials of sleep. This program includes

1)  sleep compression (slowly reducing the amount of time spent in bed (not sleeping) to obtain the optimal sleep time)

2)  sleep hygiene principles focused on appropriate activities, diet, liquids prior to bed time, daytime physical and social activities, light exposure, sleep environment

3)  need to keep a sleep diary and make revisions as necessary 

The CBT program (above) was used in a 4-week program for elderly attending a Veteran’s Adult Day Health Care program.  The CBT was successful in enhancing sleep quality in elderly individuals compared to controls who received general information but not CBT.  This benefit persisted at follow-up 4 months later (Martin et al., 2017).

Reader comments on this discussion are encouraged.  Experiences that enhance sleep quality are of special interest. 

References

1.  Xie, Kang, Xu et al., Sleep Drives Metabolite Clearance from the Adult Brain Science. 18; 342(6156), 2013.

2.  Martin, Song, Hughes et al., A four-session sleep intervention program improves sleep for older adult  day health care participants:  results of a randomized controlled trial. Sleep 40: 1-12, 2017

3.  Reviews:

Jessen, Munk, Lundgaard, Nedergaard. The Glymphatic System – A Beginner’s Guide.

Neurochem Res. 40: 2583–2599, 2015.

Sun, Wang, Yang et al., Lymphatic drainage system of the brain: A novel target for intervention of neurological diseases. Progress in Neurobiology 163–164 : 118–143, 2018.

Insight 6 – More longevity building: Ways to minimize brain aging

Brain aging, Individual controls aging, , , ,

Loss of memory with age is a widespread concern

any older adults have concluded that the only age change really worth caring about is that which slowly robs them of their ability to think.  Generally, muscle weakness, loss of balance and even loss of independence are often rated as less important than the loss of mental capacity that is defined as dementia.  It is important to know that dementia is not a normal age change but rather a neurodegenerative disease that at present has no cure or well defined cause.  Since aging is the main risk factor for disease and since the environment contributes significantly to the rate of aging , not intervening with known strategies will negatively impact memory as well as overall brain function.  Therefore, for longevity building, it becomes especially critical to know the latest and best information that will help preserve brain function.  This blog reviews the science on this topic and relates proven interventions. 

Numerous tests track aging of the brain

Thinking is complicated and so there exist many tests that measure each unique aspect of mental function.  For example, there are tests to measure verbal memory, visual memory, associative memory, source memory, perspective memory, processing speed, spatial navigation, and the most complex, executive function.  Interestingly and importantly, results of many studies that assessed these various brain functions over extended periods of time (more than 30 years in some studies) showed that some components of brain function have the potential to decline while others are quite stable throughout the lifespan.  Thus brain aging appears to be “selective”.   It then becomes important in longevity building to optimize those activities which have a tendency to deteriorate.

Brain functions that remain constant with age

Brain regions – where thinking occurs

Mental functions that do not change with age include semantic memory, most aspects of language, autobiographical memory, emotional processing, and automatic memory processes. Specifically, semantic memory is the memory of facts and knowledge learned over the lifespan.  This remains stable with age although the speed with which this knowledge is retrieved may be slowed.  Language refers to things such as use of appropriate grammar rules and pronunciation.  These are not forgotten and also remain constant.  Autobiographical memory is an individual’s personal history and it, too, is unwavering with time.  Emotional processing refers to typical emotional responses to problems or difficult situations.  Emotional processing takes many forms e.g. abrupt, calm, thoughtful, anxious etc.  Individual emotional processing modes do  not change with age and for the most part, one’s emotional processing at 90 years will mirror that at 30 years.  Finally, automatic memory processes remain stable over time.  Automatic memory relates to things done with minimal mental input or done by rote or constant repetition e.g. driving a car, riding a bike, making coffee, playing tennis.  They are activities that have become so routine that they seem to be accomplished without thinking.  Instability or loss of automatic memory processes usually signals the presence of neurodegenerative disease.

Brain functions that decline with age; longevity building with proven interventions

Mental functions that weaken with age include a) a slowing of information processing speed, b) a decline in executive function, and c) a decrease in specific memory functions that include encoding and retrieval processes, associative, source finding and prospective retention.  This breaks down into the following: information processing speed refers to the quickness at which one can process and respond to information.  This decrement is highly significant since it is a major reason for accidents, mistakes and even falls.  This means that the mental response to novel situations is slowed and depending on the situation, may result in an unfavorable outcome.  Fortunately, processing speed can be improved with practice (see below).  Executive function encompasses various memory skills and abilities to use information to solve daily problems.  Thus, the age-associated decrease in executive function will impinge on important activities such as shopping, banking/finances, house management, medication oversight and meal preparation.  The decline in specific aspects of memory are not as serious as the reduction of information processing speed and executive function but are frequent complaints of the older adult such as not remembering who told me that or where the information came from (source finding memory) or not remembering the reason for doing something, for example, opening the refrigerator door (encoding and retrieval memory) or working on a project and forgetting about a future task such as to turn the oven on at specific time (prospective retention memory).  Whereas these cognitive activities tend to deteriorate with age, proven interventions of intense learning experiences can significantly reduce their loss.

Longevity building – proven interventions to slow brain aging through brain remodeling

Results of numerous animal studies and now many studies in humans using sophisticated imaging techniques such as an MRI and other scans show that brain aging can be minimized and cognitive function of the older adult can be maximized by

a) a program of aerobic exercise (Insight 4)

b) continued engagement in serious mental stimulation

c) mastery of new skills

d) making sure vision and hearing is the best possible. 

These lifestyle choices improve/maintain the connections between brain cells (neurons) and assure their survival.  The effect on the brain is referred to as brain remodeling or positive neuroplasticity. Thus these specific interventions physically alter or remodel the brain in a favorable way.

1) Longevity building with aerobic exercise

Aerobic exercise yields many benefits.  With regard to cognitive function, aerobic exercise improves blood flow to and throughout the brain, promotes formation of new blood vessels, and  improves brain metabolism, thereby reducing accumulations of neurotoxins, substances that harm or kill nerve cells.  Recently, results of animal studies, now supported by data obtained in man not only in young but also older individuals, show increased formation of nerve cells as well as more nerve connections in specific brain regions (brain remodeling).  This supports earlier studies that show a correlation with fitness and cognitive function such that the higher the fitness level, the better the score on various cognitive tests (mentioned above) and the better the brain activity as recorded by a functional MRI scan (a scan that can localize which part of the brain is doing the thinking).

2) Longevity building with participation in intellectually complex work

There is considerable debate as to whether retirement harms brain function.  Initial findings reported a significant decline in brain activity following retirement.  This implied that loss of work-related brain stimulation was a major factor in brain aging and that the continuation of intellectually complex work after retirement served to prevent this loss.  Continuation with complex intellectual activities remains important but current data point to a high degree of variability regarding brain stability after retirement.  The best studies indicate that decline in brain function is evident following retirement but the onset and rate of this decline is highly variable and depends on many factors, for example, complexity of job, health at retirement, satisfaction with the job, educational level.  What is not disputed is that:  part time work post retirement preserves cognition for a significant period of time, hence continuation of complex intellectual activities remains of importance.  Additionally, several small clinical studies show that engagement in solving of complex abstract problems reduces brain aging.

3) Longevity building with learning a new skill

Skill training is specific training for a specific task.  It includes, for example, learning a new language, learning to play a musical instrument, learning computer skills, learning to crochet, and learning to ski.   Learning a new skill, although relatively easy for an adolescent and young adult,  has generally been considered more challenging for the older adult.  However, skill learning prevents decline in brain function.  This is confirmed by studies using brain scans that show positive brain remodeling in the older adult equal to that of the young adult.  Furthermore, it is now known  that for a) skill mastery and b) long term retention, the older adult benefits from training sessions that are seriously challenging and complicated.  This approach favors the best outcome for the older adult. 

Two important clinical trials (ACTIVE, IMPACT) evaluated the effect of proprietary computer programs to improve memory, reasoning and processing speed with specific practice exercises over a 10 week period.  Both studies yielded positive results such that practice test scores in memory, reasoning and processing speed increased with these programs.   The extent to which these improvements are maintained over time has not been studied as yet but would be important to know.

4)  Longevity building with sensory enhancement

There are a number of age changes that diminish the sight and hearing of the older adult.  In the absence of disease these age changes are correctable but unfortunately, they are frequently ignored.  As a result, eye sight and hearing are compromised.  The denial of hearing loss is especially common.  What is not appreciated is that failure to correct these sensory deficiencies is a big factor promoting cognitive decline.  This is because  these deficits reduce the quality of information that is received.  Referred to as “noisy processing” the brain receives inaccurate or fuzzy information which does nothing to promote learning and intellectual stimulation.  Over the long term, little knowledge is gained, and little thinking is done, with the outcome of accelerating brain aging.  Corrective lenses and hearing aids will add measurably to optimizing brain function.

5)  Adequate sleep

Adequate sleep is an important factor in preserving cognition.  This will be the topic of my next blog which points out the relation between adequate sleep and the newly discovered filtration system in the brain that removes neurotoxins.  This is a potential link between sleep, cognitive decline and neurodegenerative diseases.