Importance and Harm of AGEs

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

Blog 22 Introduction

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

Initial Importance and Harm of AGEs

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

External AGEs – Generated in Foods

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

Internal AGEs – Generated in the Body

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

Internal Pools of AGEs

The body’s internal pools of AGEs are derived from

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

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

Importance of Processing of AGEs

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

Harmful Effects of AGEs

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

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

Some important consequences of AGEs are

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

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

c)  eventual heart and kidney failure and

d)  sun-exposed wrinkles and sags. 

Avoidance of AGEs

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

Relative Amounts of AGEs in Select Food Items

Conclusions

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

References

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

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

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

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

Inappropriate Medications for the Elderly

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Blog 21 –  Adverse Drug Reactions, Part II

Introduction

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

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

Potentially Inappropriate Medications – Origins

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

Potentially Inappropriate Medications – Reasons for drug selection

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

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

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

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

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

e)  require extremely careful dosing due to kidney disease

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

Potentially Inappropriate Medications – Specific classes and drugs

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

Proton Pump Inhibitors

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

Benzodiazepines

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

Antipsychotics

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

Future Steps

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

Common Sense Approach to Avoidance of ADRs

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

Conclusions

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

References

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

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

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

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

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

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

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

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

Drug Use In The Elderly: Adverse Drug Reactions

Adverse Drug Reactions, Individual controls aging, , , ,

Blog 20- Introduction

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

What Are Adverse Drug Reactions ?

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

Reasons for Adverse Drug Reactions in Elderly

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

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

2.  Disease reduces organ function needed to adequately process drugs

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

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

5.  Inappropriate prescribing by physicians    

Issues 1-4    

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

Issue 5

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

1.  Age Changes May Influence Adverse Drug Reactions

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

How drugs are handled in the body

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

Absorption:   

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

Distribution: 

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

Metabolism: 

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

Elimination:

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

1b.  Significant PD changes occur with age. 

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

2.  Effect of Disease on Adverse Drug Reactions

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

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

3.  Polypharmacy produces ADRs

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

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

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

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

Potential Causes of Adverse Drug Reactions

Conclusions

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

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

Stress Response and Sugar Control

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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

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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

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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

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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.