Which Longevity Pharmaceuticals & Supplements Work and Why?
Several drugs reduce/delay the effects of aging via a mitochondrial chemical complex similarly to exercise and calorie restriction.
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Why does no one live to 120 years? Similarly, and more importantly for us old-timers, why is it that almost everyone that reaches a very advanced age of around 100 years is stooped, shuffling or wheelchair-bound, and a significantly diminished version of their former & younger selves?
As the mortality distribution chart below shows, after around the age of 30, US male probability of death in any year increases exponentially, peaking at around 90 years of age. After that peak virtually all survivors die in around 15 years.
Like most other animals, humans display senescence, which on the organism level is the increased mortality and gradual deterioration of all organs and functional characteristics of organisms as the individuals age.
The seemingly coordinated multi-organ deterioration that accelerates with age has led many scientists to theorize that the aging process is programmed or controlled by an internal clock. Andre Martins argues convincingly that aging is an evolutionary adaption that allows a species to adapt faster than similar species with longer lifespans.
Regardless, the tremendous advances in genomics and medical knowledge generally over recent decades has prompted many, especially in bio-hacking communities, to ask if it is possible to utilize chemical compounds to significantly exceed natural healthspan limits, where healthspan can be defined as the period of one’s life that one is healthy.
The answer appears to be YES. Several compounds likely delay and possibly reverse some aging effects.
Below is a summary of likely benefits and possible side effects of some of the most popular supplements and pharmaceuticals. Before that section is a more in depth discussion of the chemistry and biology impacting aging.
Those who just want to get to the evidence for or against each drug can feel free to skip the next section on the Science of Aging and go right to the Pharmaceuticals and Supplements section.
Science of Aging
Critical Biomarkers of Aging
In addition to the wide variety of familiar age induced medical conditions, including cancer, dementia, cardiovascular disease (CVD), arthritis, diabetes, high blood pressure, and sensory degeneration, aging coincides with changes in a wide variety of biomarkers. These include DNA damage from oxidants, shortening of telomeres (protective caps on chromosomes), epigenic changes (turning on/off of genes), loss of histones (key amino acids), hormone changes and many more. The wide variety of changing biomarkers linked with aging have lead to significant disagreement between medical scientists as to the “causes” of aging.
However, research over the last several decades has increasingly shown the critical importance of mitochondrial dysfunction and the appearance of senescent cells as the most important, and possibly reversible, biological factors controlling aging.
Mitochondria are the small organelles in all human cells (except red blood cells) that provide the cells with energy. They also help control many cell functions, such as signaling and the cell cycle, including cellular differentiation, cell growth, and cell death. Cells typically have tens to thousands of mitochondria.
As we age our mitochondria do not function as well as when we are younger. Poorly functioning mitochondria produce more Reactive Oxidative Species (ROS), which damage genes and other parts of the cells. Most readers will have heard of or been persuaded to eat more foods rich in antioxidants, with the presumption that these combat the long recognized harmful effects of ROS.
Consequently, with age we have an increasing number of senescent cells, which are cells that have become swollen with debris and poorly functioning organelles and which have reached the final stage of the cell cycle, just prior to cell death.
Normally, especially in healthy young cells, a process called autophagy (or mitophagy when defective mitochondria are removed) works to clean up cell components, like mitochondria, that are not functioning properly. However, as we age a chemical complex called mTOR (mechanistic target of rapamycin) increasingly blocks cell autophagy and mitophagy. Additionally, senescent cells secrete high levels of unhealthy, inflammatory cytokines, immune modulators, growth factors, and proteases in a phenomena known as SASP, which, in addition to causing age related diseases, induce nearby healthy cells to transition to the senescent state in an unhealthy cascade.
Genes
Not surprisingly, individual variations in genes play a significant factor in longevity. The New England Centenarian Study (NECS) based at Boston University’s School of Medicine has assembled the world's largest database of centenarians (those 100+) and their families in the world.
Researchers at the NECS have discovered that longevity runs in families. They have identified over 130 genes that contribute to longevity. One of the most interesting discoveries is that other than a few rare exceptions, centenarians have just as many disease-associated genetic variants as the average population. Or in other words, this special group of individuals have gene mutations that could produce cancer, diabetes, dementia, and other diseases of old age, but various combinations of the 130 anti-aging genes provide some mechanism for members of this group to fight off these typical ravages of old age.
Still, NECS researchers estimate that genes only affect around 20% of longevity with the remaining 80% controlled by environment and lifestyle.
Calorie Restriction
Calorie restriction (CR), the reduction of caloric intake without inducing malnutrition, is the most reproducible method of extending health and lifespan across numerous organisms, including humans. CR reduces/delays many age related diseases and improves the biomarkers discussed above.
For example, researchers have found that moderate CR extends the lives of mice by 10%, and when combined with time restricted feeding, the CR mice live 35% longer. Other research shows that CR applied to older mice protects against cognitive decline and neurological diseases like Alzheimer’s Disease (AD). The CR mice don’t just live longer but also have reductions in all age related diseases. Short term (2 yr) studies in humans confirm benefits of moderate CR.
CR slows aging primarily by suppressing/inhibiting mTOR, thereby reducing the body’s inflammatory response and restoring autophagy, including mitophagy, which is the removal of defective mitochondria from cells. CR also reduces the number of senescent cells.
Exercise
We all know that exercise is good for us. However, many people don't realize just how beneficial it is. Exercise does not just strengthen the muscles, bones, tendons, etc. being used (including the vascular system). It also stimulates the immune system and reduces incidence of most age related diseases including cognitive decline.
As one recent paper documents:
“Over the last few decades, studies have shown that 150 min/wk of moderate or 75 min/wk of vigorous-intensity aerobic PA (physical activity) reduces the average otherwise sedentary person’s relative risk of all-cause mortality by ∼50%, and that additional exercise has further but diminishing benefits. PA yields dose-dependent reductions in the risks of numerous diseases including hypertension, cardiovascular disease (CVD), type 2 diabetes, Alzheimer’s, and many cancers. PA also slows senescence”
Exercise, just like calorie restriction (CR), inhibits mTOR (indirectly), resulting in improved autophagy, reduction in senescent cells, reduced inflammatory response, and delayed aging throughout the body.
Pharmaceuticals and Supplements
Rapamycin
The critical chemical complex involved in aging (discussed above), mTOR (mechanistic target of rapamycin), is named for this drug, as the effects of mTOR were first illuminated by research into rapamycin, which inhibits (targets) this important signaling complex.
Rapamycin (Sirolimus) was first isolated in 1972 in samples taken from Easter Island. It was originally developed as an antifungal agent. However, use as an antifungal was abandoned when it was discovered that continuous use suppresses the immune system. As a consequence, it is now primarily used to coat coronary stents, prevent organ transplant rejection, treat a rare lung disease called lymphangiole-= iomyomatosis, and treat perivascular epithelioid cell tumor (PEComa).
Rapamycin extends the life span and reduces age-related diseases in a wide variety of animal models. The survival plots below clearly show the survival benefits of rapamycin combined with acarbose given to lab mice starting at 9 months of age (around 21 in human years). The rapamycin and acarbose fed mice (red lines) lived a median of 28% and 34% longer for females and males, respectively.
Rapamycin does not just increase mouse median life span but also slows aging! As Wilkinson and coauthors report in another paper:
Our results show that rapamycin-treated mice are delayed in the development of many forms of age-related pathology, including degenerative changes in the liver and heart, proliferative lesions of endometrium and adrenal gland, and alterations in tendon elasticity. The age-dependent decline in spontaneous activity was also diminished in rapamycin-treated mice, although the effective dose differed between males and females.
The greatest anti-aging benefit of rapamycin may be its ability to slow the ubiquitous cognitive decline associated with aging. Lab mice fed rapamycin continuously from 2 months of age show significantly less cognitive decline at 18 months than controls. A recent paper has demonstrated that rapamycin blocks progression of vascular, metabolic and early cognitive deficits in mice genetically engineered to have the same APOE4 gene variant that is responsible for the majority of early Alzheimer’s Disease (AD) in humans!
Astute readers may wonder if it is wise to voluntarily take a pharmaceutical that suppresses the immune system and can have other side effects. For most of us it would not be a good idea to take rapamycin at the doses given to transplant recipients (10 mg/day). While generally safe, daily use at high doses can cause serious side effects like liver damage in addition to making the user more susceptible to infection.
However, researchers have found that intermittent rapamycin use in animal models can provide anti-aging benefits at much lower cumulative doses so that side effects are very rare and the immune system is not suppressed. As a result, intermittent rapamycin use has become quite common in biohacking communities. Several websites are devoted to this community.
Randomized human trials with placebo controls to test the anti-aging efficacy of rapamycin are underway but results will take years. A recent survey of current and past off label (for anti-aging) rapamycin users found the only statistically significant side effect of low dose intermittent use was a doubling in the self-reported instances of mouth ulcerations (canker sores).
Many medical professionals would argue against human off-label use without proof of efficacy in humans. However, given the well known long term safety profile in transplant patients (at high doses) and the minimal self-reported side effects for low dose intermittent use in the recent survey, the potential (benefit / risk) ratio is high for many individuals, particularly for some groups. such as those with AD or the AD allele APOE4, ALS, Parkinson’s Disease, or one of the approximately 6000 Orphan Diseases, many of which are sensitive to the mTOR signaling pathway.
For example, one of the of the leading proponents of using rapamycin off-label is Dr Alan S. Green, now 80 years old, who has been using rapamycin to treat his rare Apical Hypertrophic Cardiomyopathy disease since 2016. He also still practices medicine, having devoted his practice to combating aging. He has 1,250 patients using rapamycin.
Rapamycin Summary: Intermittent rapamycin use likely provides some anti-aging benefit, particularly related to cognitive decline, with a very low risk profile.
Metformin
Metformin, derived from the French Lilac, is a commonly used treatment for type 2 diabetes and obesity. Like rapamycin it is considered a Calorie Restriction Mimic (CRM), because Metformin “tricks” cells into indicating low cellular energy status, thereby activating AMPK and sirtuin proteins, which in turn inhibit mTOR.
Metformin was approved for use in the United States in 1995, with more than 30 million prescriptions filled in the United States yearly.
Metformin anti-aging data is mixed.
A 2014 paper found that diabetics treated with Metformin lived longer than a matching cohort that didn’t have diabetes! However, a more recent paper using Danish health data refutes the claim. Both paper have limitations, the biggest being that the test subjects are human and not lab rats, and therefore more prone to deviate from the experimental protocol, especially for an experiment of many years duration.
In a NIA (National Institute of Aging) 2016 mice study, Metformin used alone had a modest increase in life span, but only in male mice. When Metformin was combined with rapamycin there was a very dramatic lifespan increase in one of two strains of mice. Male and female mice had a 24% increase in median life span and 10% and 17% increase in maximum life span. This was an impressive increase over rapamycin alone.
Metformin has been shown to slow the epigenic clocks in 32 diabetic patients. It has shown antitumoral effects in various cancers.
Based on the animal studies and the 2014 paper claiming longevity benefits for Metformin-taking diabetics, Metformin was a popular anti-aging pharmaceutical until recently. However, metformin has recently been shown to negatively impact some of the insulin resistance, cardiorespiratory and fitness benefits of exercise. Consequently, it is not currently utilized widely as a primary anti-aging supplement.
Resveratrol
Resveratrol is another CRM with significant evidence of anti-aging effects in humans and animals models.
Resveratrol is found in foods such as grapes, berries, pine nuts, and legumes. Mediterranean diets are rich in resveratrol and have been associated with promoting positive markers of health. For example, the consumption of resveratrol via red wine has been linked to the lower incidence of cardiovascular disease (CVD) in France despite high-fat diets.
This proposed effect on CVD is due to resveratrol’s antioxidant and anti-inflammatory effects. As with other CRMs, resveratrol inhibits cancer cell growth and has anticancer effects in multiple animal models. Additionally, resveratrol has been documented to decrease age-dependent cognitive decline and AD-like pathologies in humans. Moreover, in healthy humans, resveratrol improves cerebral blood flow and cognitive performance.
Major positives for resveratrol:
No known side effects at recommended doses (under 3g/day)
No prescription needed
Inexpensive. A 60 day supply on Amazon is $17.09 on 7/23/2023
Taurine
Taurine has become highly discussed since the release of an important research paper in the June 2023 Science magazine. As the Science Editors tell their readers:
Studying various animals, Singh et al. found that the amount of the semi-essential amino acid taurine in circulation decreased with age (…). Supplementation with taurine slowed key markers of aging such as increased DNA damage, telomerase deficiency, impaired mitochondrial function, and cellular senescence. Loss of taurine in humans was associated with aging-related diseases, and concentrations of taurine and its metabolites increased in response to exercise. Taurine supplementation improved life span in mice and health span in monkeys.
The researchers found that Taurine-fed mice of both sexes survived longer than the control mice. The median life span of taurine-treated mice increased by 10 to 12%, and life expectancy at 28 months increased by about 18 to 25%. The research also found that:
We … investigated the health of taurine-fed middle-aged mice and found an improved functioning of bone, muscle, pancreas, brain, fat, gut, and immune system, indicating an overall increase in health span.
As with resveratrol, there are no known side effects at the recommended dose ( up to 3 g/day orally). At that maximum recommended dose, a 30 day supply on Amazon is $12.34 today.
Summary
Resveratrol and Taurine likely provide anti-aging benefits, at low cost, and with essentially zero risk. I personally take both daily.
Rapamycin offers intriguing possible benefits but involves a greater commitment. Most primary care physicians won’t prescribe it off-label (mine won’t), and thus specialists and/or internet doctors must be sought out to prescribe it. Most users monitor their blood glucose, which may rise, so they can control the glucose increase with other medicines. As I said, rapamycin requires a greater commitment, but the potential payoff is great, especially for cognitive issues.
If I start taking rapamycin I’ll post an update in the future.
A well-written and insightful article. I find most interesting the coniguity of science research to the cause and perhaps prevention of aging, as aging is an inevitable part of life.
Of course diet and exercise plays a huge role in health and longevity, but i wonder how calorie restriction should be utilized in order to prevent mTOR. Is CR just a scientific term for prevention of obesity/being over-weight?
Something else to note, the FDA doesnt approve/test a large majority of supplements being sold to consumers. It's important to obtain supplements such as taurine and resveratrol from trusted sources so as not to be spending money on vegetable capsules filled with empty calories.
One final thought, for the conspiracy theorists... There is a population crisis on Earth, most notably in the Asian continent. Immigration from Asia/Middle East has swept over the world. Would longer lifespans speed up the over population of Earth? Furthermore, life longevity would not look desire-able to the people who run the world (whether they be billionaires or lizard people - depending on the conspirator). How would the US government, secret organizations, or 'lizard people' hinder the research and preventions of aging? There are already conspiracies towards Bill Gates' "Apeel" program (chemical coating over fruits and veggies) with supposed eugenic properties.
Thanks for this excellent article!
Resveratrol was tested 3 times in the NIH Interventions Testing Program (ITP) and failed to show any benefit on lifespan (contrary to acarbose, rapamycin and a few others): https://www.nia.nih.gov/research/dab/interventions-testing-program-itp/supported-interventions
Do you know by any chance if someone has already submitted a proposal to test taurine in the ITP? (See: https://www.nia.nih.gov/research/dab/interventions-testing-program-itp/application-instructions ) Anyone can request a test so I may well do it...