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Anti-Aging Medicine

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Aging TheoriesMedicine is largely an exercise in cause and effect. Because senescence has such a diffuse and multi-symptom nature and also is of such a long-term nature, it is probably the most difficult area of medicine in which to establish cause-and-effect relationships. This is one reason that theories of aging that suggest research directions are so critical to the development of treatments for age-related diseases and conditions.

The term anti-aging medicine means different things to different people. Many see “anti-aging medicine” as essentially a cosmetic or esthetics effort. We can delay the appearance of aging with tummy-tucks, face lifts, and Botox.

Another view is towards “healthy aging,” or “better aging.” We can work to extend the healthy and happy portion of our lives and decrease the length of the nursing-home-stage but not necessarily live much longer. Life-style modification including exercise and diet are frequently part of this approach. Lifestyle protocols are not very controversial; most physicians favor less obesity, healthy diet, more exercise, a generally more active life, and avoiding dangerous behaviors like smoking, alcoholism and drug abuse. There is wide respect for a “use it or lose it” concept in which exercise and activity are beneficial. Even exercising a person’s mind is thought to delay age-related mental deficits.

Finally, some are looking toward essentially treating aging, per se, and delaying the age at which manifestations of aging would otherwise appear in a particular individual. Some consider that such manifestations are reversible and that regenerative medicine could reverse or reduce some symptoms of aging including age-related diseases. Average and maximum human lifespan could be extended. Since there is little actual clinical evidence of pharmaceutically extending maximum human lifespan and this idea is unpopular in the general public and the medical community, most practitioners are careful not to make extravagant claims in this area. Treating aging, per se, might be expected to have more obvious effects on older people.

In a twist to this idea, it is widely agreed that senescence is largely an inherited characteristic and varies between individuals. The old saw goes: “If you want to live a long life, choose long-lived parents.” An anti-aging practitioner might say “Your hormone levels are not typical for a person your age and need to be adjusted. Of course, if that is a valid approach, the patient might say: “I would like to have my hormone levels adjusted to those of a typical 110-year-old or whatever levels the 110-year-old had when they were my age!” See more on hormones below.

Anti-Aging Agents

The thousands of prescription drugs are tested and certified for use in treating a particular disease or condition. However, a physician can prescribe most prescription drugs “off book” for other uses. In addition there are thousands of over-the-counter non-prescription drugs thought to be beneficial in treating some disease or condition as well as thousands of foods and substances sold by vitamin and health food stores also thought to have beneficial effects. Hard evidence of effectiveness such as double-blind clinical trials is usually much less available on the non-prescription substances.

Programmed aging theories suggest that aging is substantially the result of a biological mechanism and therefore that agents can be found that affect this mechanism just as they can be found for treating the disease and condition-specific mechanisms. As programmed aging theories become more popular we can expect to see many substances suspected of having anti-aging properties. Because it is progressively harder to establish cause and effect for anti-aging agents in longer-lived organisms such as humans a lot of the evidence will be coming from experiments with shorter-lived organisms such a mice (~2.5 years), some short-lived fish species (8 weeks), even worms and flies that may or may not be directly applicable to humans. Agents can also be evaluated by measuring their effect on senescence indicators such as telomere length, hormone levels, etc.

Non-programmed theories suggest that anti-damage agents such as anti-oxidants or anti-inflammatory agents might be effective.

The US National Institutes of Health (NIH) National Institute on Aging (NIA) is operating a search for anti-aging agents that they call the Interventions Testing Program. Oral agents are tested in mice and evaluated for effects on lifespan. This program can only evaluate a few agents per year and does not deal with injected agents or experiments that require special handling such as exercise regimens.

Human testing in elderly subjects might provide relatively rapid results depending on the nature of the aging mechanism. For example if aging is reversible, such testing may provide measurable results in a short period.

Suspected anti-aging agents include: rapamycin, metformin, resveratrol, vitamin D3, Cycloastragenol, and deprenyl.

Because some suspected anti-aging agents apparently have few side-effects large scale human trials are possible.

Blood Factors and Aging Mechanisms

Programmed aging theories suggest that aging is the result of a biological program that purposely causes or allows manifestations of aging to appear on a species-specific schedule. If this program is similar to other biological programs such as the ones involved in reproduction, or glucose metabolism, or circadian rhythms, or stress responses, then it is likely that some part of our body determines when to apply the aging function and sends signals to other parts to implement the function. These signals can be nervous or chemical (hormonal) in nature and hormone signals are typically distributed in blood plasma. Therefore, if aging is programmed we could logically expect to see “age” or “don’t age” signals (or both) in blood plasma. Indeed, many human hormones are observed to either decrease or increase with age.

Experiments have been performed in which tissue from older animals is exposed to plasma from young animals. Senescence markers were observed to change in response.

Heterochronic plasma exchange (HPE), or infusion of young plasma into old patients (or infusion of old plasma into young animals) is being explored as a way to study anti-aging effects of blood factors. The advantage of this approach is that is not necessary to understand which hormones are involved or exactly how they work in order to demonstrate an anti-aging effect. HPE trials could also result in near-term anti-aging treatments. See Young Blood Institute and Ambrosia Company.

Therapeutic plasma infusion is a recognized technique used in treatment of various diseases. However, the trials and prospects for treatments are highly controversial, at least partly because of attitudes described in companion articles.

Any signaling scheme must have means for both asserting and removing the signal. Hormone concentrations naturally decay. Some hormones are cancelled by other associated hormones and endocrinology is a complex subject. It is therefore somewhat unclear if plasma therapy would have beneficial effects for long enough to be practical. The importance of this issue depends on which hormones are actually important in aging.

American Academy of Anti-Aging Medicine

At least in the U.S. anti-aging medicine is an established medical specialty. The American Academy of Anti-Aging Medicine (A4M) is a medical specialty association like the American Podiatric Medical Association, or those supporting any other branch of medicine. From A4M literature:

“The American Academy of Anti-Aging Medicine (A4M) is dedicated to the advancement of tools, technology, and transformations in healthcare that can detect, treat, and prevent diseases associated with aging. A4M further promotes the research of practices and protocols that have the potential to optimize the human aging process.

The organization is also dedicated to educating healthcare professionals and practitioners, scientists, and members of the public on biomedical sciences, breakthrough technologies, and medical protocols through our advanced education entity: Metabolic Medical Institute (MMI).

A4M is a U.S. federally registered 501(c)(3) non-profit organization comprised of over 26,000 members across the globe, including physicians (85%), scientists and researchers (12%) , and governmental officials, media, and general public (3%), all of whom collectively represent over 120 nations.

A4M is focused on spreading awareness about innovative, cutting-edge science and research, in addition to treatment modalities designed to prolong the human life span.

The core of the NEW medicine is based on scientific principles of comprehensive medical care, which encompass many other specialties within healthcare.

A4M Provides continuing medical education (CME) and training to over 65,000 physicians and health practitioners at multiple live conferences worldwide, as well as online CME education in the functional, metabolic, and regenerative medical sciences. A4M supports advanced education, conferences, certifications, fellowships, online courses, and graduate programs.”

A4M practitioners include those supporting all of the treatment viewpoints described earlier. Many practitioners have expanded existing physician practices in some other specialty to include anti-aging medicine. With regard to pharmaceutically delaying aging there are currently (2018) two major initiatives in the A4M community:

Telomerase Activators

Telomeres are the “end caps” on chromosome molecules that tend to shorten with age. Since the 1960s age-related telomere shortening has been suspected as part of an aging mechanism. Telomerase is a naturally occurring enzyme that repairs (lengthens) telomeres. “Telomerase activators” that stimulate production of telomerase and therefore increase telomere length are in use by some anti-aging practitioners. Clinical trials show that these oral medications do increase telomere length but actual lifespan extension is much harder to demonstrate.

From Wikipedia: “The NASDAQ listed company Geron has developed a telomerase activator TAT0002, which is the saponin cycloastragenol in Chinese herb Astragalus propinquus. Geron has granted a license to Telomerase Activation Sciences to sell TA-65, the telomerase activator agent also derived from astragalus. In October 2010 Intertek/AAC Labs, an ISO 17025 internationally recognized lab, found the largest component of TA-65 to be Cycloastragenol.”

Bio-identical Hormone Replacement Therapy (BHRT)

Age-related changes in hormones are specifically suggested by programmed theories as parts of a programmed aging mechanism. Since many human hormones decrease with age and some increase with age enhancing concentrations of the former and interfering with the latter are obvious possibilities for an anti-aging treatment. However, hormone replacement (estrogen, testosterone, “steroids”) has been historically associated with significant adverse side-effects. BHRT practitioners suggest that this problem has been reduced or eliminated by using a different “bio-identical” form of the hormone(s) and using reduced dosage relative to the earlier treatments.

Conclusion: It is possible that therapies and agents that already exist have some effect in treating aging, per se, and therefore produce lifespan extension. However the extreme difficulty in establishing definitive cause and effect evidence and current unpopularity of this idea (see companion articles index) suggest that no definite medical conclusions can be expected in the near future. Plausibility of such result depends heavily on which of the many aging theories one accepts. Trials of therapies and agents that have a reasonable demonstration of safety in relatively elderly patients appear to have the best prospects for demonstrating effectiveness in this area.

Aging Theories Articles Index

 

Medical Implications of Aging Theories

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Aging TheoriesAs can be seen from the figure (U.S. mortality data), human death rates from all causes in developed countries increase exponentially starting at about age 30 and doubling approximately every ten years. We can define age-related disease or condition as one where the incidence and severity drastically increase with age to the point where aging is by far the main cause. Massively age-related diseases include heart disease, stroke, cancer, arthritis, cataracts and other vision deterioration, hearing loss, and loss of strength and balance. Alzheimer’s disease is essentially unknown in young people. Death rates for 40-year-olds are approximately twice the rates for 30-year-olds so we can consider that nominally half of deaths in 40-year-olds are caused by aging along with three-quarters of deaths of 50-year-olds and so forth. Aging and age-related diseases cause about three-quarters of all deaths in developed countries and represent more than half of medical research and health-care costs.

There is wide agreement that there are different immediate or direct causes associated with each age-related disease and condition. The immediate causes of heart disease are not the same as the causes of cancer or the causes of arthritis, etc. Western medicine is largely based on the idea that we need to find different treatments and pharmaceutical agents to treat different diseases and conditions. This approach has obviously been substantially successful in treating age-related diseases.

The current trillion-dollar question is whether or not aging, per se, although obviously the main cause of the age-related diseases is itself a treatable condition. If so, treatment of aging could be used in parallel with the existing medical paradigm in our efforts to treat age-related diseases and conditions. As described below, different aging theories suggest drastically different answers to this question.

Fundamental limitation theories, wear and tear, stochastic, etc. strongly suggest that aging is an untreatable condition. We can find treatments for individual symptoms such as cancer and heart disease but we cannot find ways to treat aging, per se, as it is the result of fundamental limitations that could not be overcome by the evolution process and are very unlikely to be overcome by medical advances.

Modern non-programmed aging theories suggest that aging is not the result of fundamental limitations but rather the result of a large number of different independent factors as explained by George Williams in 1957. Unlike inanimate objects, living organisms obviously have many biological mechanisms for repairing or preventing damage. Wounds heal; dead cells are replaced; immunity is acquired, and so forth. Therefore humans and other organisms reasonably would have developed biological mechanisms to delay the appearance of cancer, other methods for dealing with the different damage mechanisms associated with heart disease, and myriad other mechanisms for delaying the occurrence of other age-related diseases and conditions.

This concept explains why different mammals have such different internally determined lifespans while having very similar biochemistry and similar symptoms of aging. This idea assumes that all of the different maintenance and repair mechanisms each presumably independently evolved and retained just the effectiveness needed to deliver the minimum necessary species-specific internally-determined lifespan called for by modern non-programmed theories based on Medawar’s evolutionary mechanics ideas.

These concepts support the accepted idea that we can find different ways to treat each specific age-related disease. However, these concepts suggest that there is some ultimate age beyond which further progress in extending human lifespan would cease because eventually every aging symptom would appear at catastrophic levels. They further suggest that there is no treatable common factor behind age-related diseases and conditions. These theories therefore support the current medical paradigm of ever-increasing specialization by disease, disease sub-type, and even personal disease variety.

Modern programmed aging theories suggest that a second path toward combating age-related diseases and conditions exists. These theories propose that the age-related diseases and conditions are coordinated by a biological aging program that stages the appearance of aging symptoms to result in a particular optimum lifespan for each species population. In addition to finding better ways to combat each particular disease we can look for ways to interfere with the aging program and therefore generally delay or reduce the severity of age-related diseases especially in older individuals. If valid, this is an exciting development because two different approaches can be used against age-related diseases. Because the anti-aging approach is new, we could reasonably expect “low hanging fruit” and rapid progress.

The effectiveness of an attempt to interfere with the aging program depends on one’s concept of the nature of that program and specifically the degree to which the program is common to the many age-related diseases and conditions and the extent to which the common program can control each symptom. For example, if senescence is controlled by a program similar to the one that controls mammal reproduction, and aging is a genetically programmed phase of life, then we could expect rather dramatic results. If we wanted to delay or advance puberty that would certainly be possible. There is considerable theoretical thinking and empirical evidence suggesting that, like reproduction, aging is controlled by a complex common program involving signaling (hormones).

There is fairly wide sentiment to the effect that aging can be generally delayed by exercise and perhaps by caloric restriction. This idea conflicts with non-programmed “damage” theories because exercise and caloric restriction would be expected to increase, not decrease, damage. Many other observations support programmed aging.

For more discussion of the nature of the aging program and supporting evidence see:

Externally Regulated Programmed Aging and the Effects of Population Stress on Mammal Lifespan

Aging Theories Articles Index

 

 

Why do we age?

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Aging TheoriesThis is one of the longest-running and still-unresolved questions in science. There are hundreds of competing biological aging theories and no scientific agreement that any one of them is correct. There is not even any agreement on the fundamental nature of aging. Is aging something that happens to your body as a result of forces of nature or is aging something your body does to itself like growth or puberty? It turns out that the choice of aging theory is almost entirely driven by one’s choice of evolutionary mechanics theories or the theories describing how the evolution process operates.

Observations Concerning Lifespan and Senescence

There are a number of observations that are essential to modern aging theories. Because aging theories are essentially subsets of evolution theory, and because evolution theory applies to all living organisms, scientifically credible aging theories need to consider multi-species observations about aging and internally determined lifespan such as:

  • Lifespans and senescence vary greatly between species. Mammal lifespans vary over more than a 200 to 1 range between some whales (> 200 years) and some mice (< 1 year). Fish lifespans vary over a range of more than 1300 to 1.
  • Symptoms of aging tend to be similar but not identical between related species. Dogs and humans, even though their lifespans differ by about a factor of seven, suffer from very similar symptoms of aging like cancer, heart disease, stroke, arthritis, mobility and sensory deficits, etc.
  • Internally determined lifespan resembles an evolved trait: It varies somewhat between individuals and to a much larger degree between species.

There is extremely good scientific agreement on most aspects of Darwin’s evolution theory as described in Darwin’s book of 1859 and currently taught. However, despite the more than 150 intervening years there is still disagreement regarding arcane evolutionary mechanics details. Specifically, does the evolution process operate to benefit individual members of a species population or does it operate to benefit a population of individual members of a species? This obscure detail might well appear to be trivial and in maybe 99 percent of observations of organism traits makes no difference. This is because evolved inherited organism design characteristics or traits that benefit the ability of an individual to survive and reproduce also benefit the ability of a population of those individuals to avoid extinction and grow. Aging is one of the exceptions as described below.

This obscure detail is crucial to the aging theory issue. A high-school biology student could tell you that Darwin’s theory says that the evolution process causes organisms to acquire traits that cause possessing individuals to live longer and breed more than non-possessing individuals, and further that aging obviously does not cause an aging individual to live longer and breed more than an otherwise identical non-aging individual. On the other side, some theorists have now suggested at least a dozen ways that aging helps a population despite being adverse from an individual’s viewpoint and, so far, there has been no scientific disagreement with any of these ideas. Therefore the population vs individual issue is the controlling issue for aging theories as well as some other observations. The evolutionary mechanics issues have resulted in four classes of aging theories:

Simple Deterioration or Damage Theories

Simple deterioration theories suggest that aging is simply the result of the same sort of processes that cause gradual deterioration in non-living objects and systems. Physical processes include mechanical wear and tear, and micro-injuries. Perhaps aging results from nuclear background radiation. More chemistry-oriented causes might include oxidation, damage from free radicals, telomere shortening, random damage to DNA, etc. These theories are still popular in the general public: “We wear out” (like automobiles or sewing machines or exterior paint). There is little scientific disagreement with the idea that deteriorative processes could be parts of the mechanisms that cause aging.

However, major problems quickly became apparent in the bioscience community:

  • Living organisms obviously possessed many maintenance and repair functions that acted to prevent or reverse damage. Wounds heal, shed hairs are replaced, worn nails and claws regrow, blood and skin cells are continuously replaced.
  • Living organisms were capable of evolving changes in their designs that act to reverse or prevent deterioration.

Obvious question: If aging is the result of simple deterioration processes, why didn’t organisms evolve ways to overcome those processes as they had already demonstrated? This problem led to the fundamental limitation theories.

Fundamental Limitation Theories of Aging

As described above, Darwin’s evolutionary mechanics concept suggests that the force of evolution is toward developing non-senescent species. Individual members of a species that do not possess any internal limitation on their reproductive lifespans would be able to live longer and breed more than competing senescent individuals. Obvious question: Why, given billions of years of evolution, are there still senescent species? Obvious answer: a longer lifespan is physically or chemically impossible because of some law of physics or chemistry. Of course there are books full of laws of physics and chemistry and human aging is a gradual general deteriorative process superficially similar to aging in machinery and exterior paint. The second law of thermodynamics (entropy) is often cited in connection with aging. Today, because of their good fit with Darwin’s mechanics and human aging, fundamental limitation theories are still popular with the general public and some physicians.

However, fundamental limitation theories utterly fail to explain multi-species observations about aging. Why would a 50 Kg dog be seven times as affected by some law of physics or chemistry as a 50 Kg human?  Why would a parrot live six times longer than a crow? Articles about fundamental limitation theories typically ignore non-humans and target people who are mainly interested in human aging.

Aging Theories that Propose a Limit to Lifespan Benefit

In 1952 Nobel-prize-winning biologist Peter Medawar proposed a modification to Darwin’s mechanics to the effect that the evolutionary benefit of living longer and breeding more declined with age in a species-specific and population-specific manner, and further that internally determined lifespans needed by members of a wild species population depended on external circumstances such as predation, food supply, and habitat surrounding the population as well as internal traits such as age-at-puberty and other reproductive behaviors. Evolution is all about competition and “survival of the fittest” under wild conditions. We can easily imagine that there would be a species-specific age at which virtually no individual members of a population would remain alive because of external causes of mortality such as predators, infectious diseases, harsh environment, lack of food, or any of the myriad other causes of death in wild organisms. Consequently there would be little evolutionary motivation to develop the internal ability to live longer than a species-specific age. A population of aging individuals might be essentially as successful as a population of otherwise identical senescing individuals. This led to a family of modern non-programmed aging theories to the effect that each species only needed the internal capability for achieving a particular internally-determined lifespan and therefore only evolved and retained the ability to live that long. These theories provide a much better match to multi-species observations and are currently popular in the gerontology community.

However, subsequent (1957) widely accepted analysis by George C. Williams suggested that the deteriorative effects of aging occurred too early in life to have no negative effect on a population. Deterioration in strength, speed, and sensory acuity would affect an organism’s ability to survive and compete well in advance of the age at which most individuals would be dead from external causes and thus negatively affect survival of the population. Wild animal studies confirmed Williams’ analysis. This led to the conclusion that senescence must create a benefit for a population that offset its negative effects.

There are multiple competing theories that propose different solutions to this problem including the mutation accumulation theory, the antagonistic pleiotropy theory, and the disposable soma theory, and no agreement as to which is correct. Proponents of programmed aging (below) have described many logical and observational issues with each of these theories. Articles about mammal aging theories based on Medawar’s and Williams’ concept typically ignore non-mammals.

Programmed Aging Theories

Programmed aging theories are based on modifications to Darwin’s mechanics (and extensions to Medawar’s ideas) to the effect that aging, although adverse to individuals, benefits populations and that therefore species evolved biological mechanisms that internally limit their lifespans. Aging is an adaptation that serves an evolutionary purpose just as eyes, ears, and toes serve a competitive purpose in a wild population. Although programmed aging was first formally proposed in 1882, it was largely dismissed as obviously scientifically ridiculous because of the gross and direct conflict with Darwin’s mechanics until about 2002. Various analyses of Darwin’s mechanics confirmed that of the student: Darwin’s mechanics concept does not support population benefit or dependent programmed aging theories. The idea that we possess what amounts to an evolved suicide mechanism or “biological self-destruction clock” that limits an individual’s ability to survive and reproduce grossly conflicts with the nature of evolution as most people understand it.

However, a number of developments (and non-developments) have exposed additional issues with Darwin’s mechanics concept that specifically support population benefit and programmed aging:

  • Despite more than 150 years of effort theorists have been unable to produce an aging theory that is fully compatible with Darwin’s mechanics and simultaneously even semi-plausibly explains multi-species aging observations. Modern non-programmed (non-adaptive) aging theories are based on post-1952 modifications to Darwin’s mechanics that are more population-oriented.
  • In addition to senescence, other observations conflict with Darwin’s mechanics. These include sexual reproduction, individually adverse mating rituals and other behavioral observations such as animal altruism, and existence of apparently non-aging species. This led to the post-1962 development of multiple population-oriented mechanics theories including group selection theories and evolvability theories.
  • Genetics discoveries have exposed multiple issues with Darwin’s mechanics and support population-oriented mechanics and programmed aging theories. More generally, genetics discoveries suggest that the evolution process is much more complex than previously thought.
  • Some very explicit and obviously programmed suicide mechanisms have been discovered in non-mammals such as octopus and roundworm. Genetically engineered roundworms have been produced that live ten times as long as the wildtype!

Current Status of Aging Theories

The present situation is that current published science no longer supports the idea that programmed aging is impossible. The academic gerontology community still largely supports non-programmed theories based on Medawar’s/ Williams’ modifications to Darwin’s mechanics because such theories provide a better fit to multi-species observations than the fundamental limitation theories while not being so obviously incompatible with Darwin’s mechanics. Commercial entities (e.g. pharmaceutical companies) have begun to make major investments in research based on programmed aging theories.

Many non-science factors bias public and academic thinking toward non-programmed aging theories. For example, most people are trained in Darwin’s mechanics theory as the only science-based theory. Only a tiny fraction of these people are trained in modern population-oriented theories and dependent programmed aging theories or their supporting evidence and logic.

Because they predict that very different biological mechanisms are responsible for aging, programmed and non-programmed theories suggest very different medical research paths could be employed toward treating massively age-related diseases and conditions.

For more on evolutionary mechanics and the case for population-oriented theories and programmed aging theories see:

Evolvability, population benefit, and the evolution of programmed aging in mammals.

Aging Theories Articles Index