The Most Promising Longevity Drugs To Date
A Review of Test Results in Animals and Applications in Humans* — Update 12.2023
During its first several decades, up until the early 2000´s geroscience was fighting tooth and nail against the widespread notion that aging is non-malleable — a mishmash of complex processes that cannot be slowed or reversed, certainly not with a single drug.
Things began to change after the discovery of genes that seemed to affect aging in model organisms, such as worms. Genes encode proteins that act on specific targets — and this action can theoretically be mimicked by a drug. But how do we find such a drug?
Why Mice Are Used in Labs
If your goal is life extension, it is almost impossible to run a proper human trial. As humans are so long-lived already, researchers would probably need for example to monitor between 500 and 1000 70-year-olds for 5–10 years to get any meaningful results. So, instead of measuring lifespan, scientists use various biomarkers of aging, such as epigenetic clocks — tests that measure biological age. Another way to do this is to look for changes in the age of onset of several age-related diseases at once. This was the essence of TAME (Treating Aging with Metformin), the first large-scale human trial of a candidate anti-aging drug.
Thankfully, to more quickly test molecules that might be used in fighting aging, we have mice. These tiny mammals have been used in laboratory testing as early as the 17th century, contributing significantly to our understanding of aging and the ways to fight it. The biology of mice closely resembles that of humans, but their maximum lifespan is about three years, which makes testing anti-aging interventions easy.
Though mice are widely considered good models for laboratory studies, the results of mouse trials are not always 100% translatable. Drugs that have shown good results in mice can fail in human trials, especially when tested in artificial models. For example, dozens of candidate drugs that showed promise against Alzheimer’s disease in mice have failed, probably because mice don’t actually develop Alzheimer´s, and researchers had to use imprecise genetically modified models. This is also the reason why geroscience has mostly moved away from mouse models with artificially accelerated aging and toward naturally aging wild-type mice. Scientists hope (not unreasonably) that natural aging processes are sufficiently similar in mice and humans.
The Gold Standard
Almost 20 years ago, the National Institutes of Health (NIH) via the National Institute on Aging (NIA) rolled out the Intervention Testing Program (ITP), a multi-institutional study investigating treatments that extend lifespan in mice.
The ITP is an attempt to standardize and simplify not just how we measure the effects of these interventions on mice, but also what we measure. Sometimes, researchers run dozens of tests and try dozens of metrics with the goal of obtaining a positive result that they can publish to great fanfare. The ITP, on the other hand, was designed to provide an answer to one simple question: does the intervention extend lifespan in genetically heterogeneous mice? And since a major goal of the project is to provide critical tests of anti-aging approaches, all data is published, including negative results.
Several other design features increase the robustness of ITP trials. For instance, the ITP uses mice that are genetically unique but within a defined genetic pool. This results in higher variability than in the commonly used inbred strains and makes the experiments more life-like.
Samples sizes are significantly larger than in most studies: a typical ITP trial includes 132 males and 98 females in the study group and twice as much in the control group (increasing the size of the control group is a cheap way to boost statistical power) A not-so-fun fact: the reason for the uneven male/female distribution is that researchers usually lose several male mice to fighting.
But perhaps the most important feature of the ITP is that its trials are run simultaneously in three different top-tier research facilities, which, according to one of the ITP founders, Richard Miller, results in ‘instantaneous reproducibility’ (you can get a deeper understanding of the ITP from this interview with Miller).
All these qualities combined make the ITP the current gold standard for aging research.
So, Has Anything Worked?
After this lengthy introduction, you probably have one question in mind: have scientists found anything that slows aging? As a matter of fact, they have.
The ITP has so far tested dozens of compounds, and some of them have indeed extended lifespan in mice. Let’s do a quick tour.
Aspirin
Back in 2004, at the dawn of the ITP, good old aspirin was found somewhat effective, producing a statistically insignificant 4% increase in maximum lifespan and a significant 8% increase in median lifespan in males, but not in females. Not surprising, considering systemic inflammation is one of the underlying processes, and thus a hallmark, of aging. Since the effect was small, aspirin was abandoned in favor of time and resources being spent on more promising candidates — a wise choice as its minimal effect could not be repeated in follow-up studies with other dosages. So questions remain as to whether there was any real effect at all.
Rapamycin
Soon after aspirin, rapamycin became a candidate due to promising results in worms and flies. Rapamycin — which targets multiple hallmarks of aging — has been shown to improve the aged heart, brain and immune system in rodents. First approved by the FDA in 1999 to prevent graft rejection in renal transplantation, rapamycin is produced by bacteria found on the soils of Easter Island, originally named Rapa Nui — giving the compound its distinctive name.
Today rapamycin is one of the best-known molecules in the longevity field. It works, at least in part, by inhibiting mTORC1 (mammalian target of rapamycin complex 1) which regulates cellular growth signaling and autophagy. Simply put, rapamycin tells cells to switch from growth to repair and maintenance.
Already in the first ITP study initiated in 2005, rapamycin delivered impressive results, extending maximum lifespan in a sex-dependent manner: by 9% in males and 14% in females.
Interestingly, a glitch in the study yielded both unexpected and incredible results. Back then, candidate anti-aging drugs were mostly tested on young mice. Scientists were convinced that late-stage interventions could only produce modest effects, causing potentially effective drugs to fail the trial and be rejected. With rapamycin, the researchers tried for months to fine-tune its absorption. So by the time they were done, the mice allocated for the trial were already 20 months old (roughly 60 in human years) at the start of the treatment. As a result, rapamycin increased their remaining lifespan by more than 50%.
The ability of rapamycin to extend lifespan so dramatically, even when given later in life, became one of the most important discoveries in geroscience at that time. Later, rapamycin in similar dosage was also tested in mice starting from 4 months of age. Amazingly, the results closely resembled those of the late-stage treatment. In yet another ITP study, in 2009, rapamycin administered to young mice in a higher dose led to a maximum lifespan increase of 8% in males and 20% in females and a median lifespan increase of 22% in males and 28% in females. In contrast to many other longevity molecules, rapamycin works better in female mice than in male mice. As of today, rapamycin’s longevity effect in mice has been confirmed by at least seven trials.
ITP data shows that the combination of rapamycin with well-known diabetes drugs like metformin or acarbose does further improve rapamycin’s lifespan increasing properties. While for example metformin alone does not have significant effects on lifespan its combination, metforming and rapamycin, increases median lifespan in females and males by 23% (the effect of rapamycin alone with the corresponding dose is 18% for females and 10% for males respectively). Even better effects were reported for the combination of acarbose and rapamycin with 37% increase in median lifespan for males and 28% in females. The effect sizes are among the biggest ever recorded for lifespan increasing drugs.
Rapamycin´s Application in Humans
Rapamycin is currently used with immunosuppressants in transplant patients to avoid organ rejection, and some doctors may be prescribing rapamycin off label already, as an anti-aging supplement particularly to prevent/delay Alzheimer’s and treat osteoarthritis.
Like some other anti-aging compounds being studied, rapamycin has shown multiple benefits in animal models. Double-blind placebo controlled human trials are also underway: Rapamycin — Effects on Alzheimer’s and Cognitive Health (REACH), which studies the effects of rapamycin on mild cognitive impairment and Alzheimer’s; and Participatory Evaluation (of) Aging (With) Rapamycin (for) Longevity Study (PEARL), wherein the anti-aging effect of the drug is being tested.
Although no results have been published yet, we at Apollo Health Ventures believe that rapamycin holds great promise, and we are very excited about these studies. Apollo Health Ventures was the first investor in Aeovian, a San Francisco Bay Area-based research stage biopharmaceutical company aiming to discover, develop and commercialize innovative therapeutics for the treatment of rare and age-related diseases. Aeovian is building the next generation of so-called rapalogs (analogs or variants of rapamycin). The company secured follow-on funding from San Francisco-based funds Sofinnova and Venbio and plans to initiate human clinical trials.
Acarbose
Acarbose is another FDA approved drug, used to treat Type 2 diabetes. Rather than diminishing the overall glucose intake, it flattens after-meal glucose spikes by preventing the breakdown of starch into sugar. Your body still gets all the sugar, but more gradually. According to an alternative theory of how acarbose extends lifespan, starch that was stopped by acarbose from being absorbed in the small intestine, then proceeds to the large intestine and the colon, where the gut microbiome transforms it to beneficial short-chain fatty acids.
When first tested on 4-month-old mice, acarbose delivered solid results. Male maximum lifespan was increased by 11% and female lifespan by 10%. In median lifespan, males enjoyed a much greater hike of 22%, but the increase in females was just 5%. Follow-up studies showed that acarbose works about half as well when given later in life.
Update May 2023: Recent data from the ITP published by end of 2022 showed that combining acarbose with rapamycin led to 37% median lifespan extension in males, the best result ever produced in the ITP program. In females adding acarbose to rapamycin showed only a smaller synergistic effect. This does not come as a surprise: Compared to males, acarbose alone showed smaller lifespan enhancing effects in females. The combination achieved an increase of 28% in median lifespan.
Acarbose´s Application in Humans
Acarbose has been on the market for about 20 years. It is used in combination with diet and exercise. Among its hallmarks is its ability to decrease Hba1c (glycated hemoglobin, or simplified average blood sugar) levels. Higher Hba1c levels indicate increased risk of long-term complications from diabetes. Acarbose can also help with weight loss and is thought to lower the risk of cardiovascular diseases. Its use is limited due to some gastro-intestinal effects which can result in bloating. Some scientists say this effect on the microbiome can even be one of the positive effects of acarbose (see here).
Additional studies which have shown a positive effect from Acarbose on weight an Hba1c can be found here:
- Impact of Acarbose on Diabetes
- Effect of Acarbose in Type 2 Diabetes
Canagliflozin
An anti-diabetes drug similar to acarbose, canagliflozin also fights glucose spikes, though it does so via an entirely different mechanism. The drug blocks SGLT2, a glucose transporter found in the kidneys. Canagliflozin extended maximum lifespan in male mice by 9%, with no effect on females. The success of both acarbose and canagliflozin underscores the importance of avoiding glucose spikes, which can be achieved via a healthy diet (though Peter Attia says he occasionally took an acarbose pill before gorging on pizza).
Canagfliflozin´s application in humans
In addition to its glucose-lowering action, canagliflozin has been linked to a 31% decrease in heart failure hospitalization and cardiovascular mortality in diabetes patients. In another study, empagliflozine, also an SGLT2 inhibitor, was shown to increase life expectancy in diabetes patients having established cardiovascular disease. Due to those enviable qualities, canagliflozin and other SLGT2 inhibitors (empagliflozin, ertugliflozin, dagagliflozin) are widely prescribed to diabetes patients and sold by several big pharma companies such as Pfizer and AstraZeneca, bringing in roughly $7 billion in annual sales.
17-α Estradiol
A weak estrogen and a 5-α reductase inhibitor, 17-α estradiol has been shown to improve metabolic function, enhance insulin sensitivity and reduce fat and inflammation in old male mice without causing feminization. It is considered “non-feminizing” due to its reduced affinity for estrogen receptors. In studies, the treatment started with middle-aged mice (10 months of age) and increased male maximum lifespan by 12% and male median lifespan by 19% but had no effect, positive or negative, on females. These results were largely recreated in a subsequent ITP study. Moreover, the latest data shows that, like rapamycin, 17-α estradiol works well even when given later in life. The drug gave male mice a boost of 19% in median lifespan and 7% in maximum lifespan when started at 16 months, but the mechanism of the drug’s anti-aging action is still unclear.
17a Estradiol´s Application in Humans
As 17-α estradiol has been shown to be effective against hair loss, that is its sole medical application as of today. Further research is needed to fully understand the drug’s potential.
We at Apollo Health Ventures are very optimistic, given that 17-α estradiol is one of only a handful of drugs that caused life extension in ITP trials. Due to the promising results in animals Apollo Health Ventures (Apollo.vc) has started the company Apollo Alpha Inc. and is currently working on developing 17-α estradiol as a human drug.
Astaxanthin
The natural compound Astaxanthin belongs to the group of carotenoids and is probably known to most people because it is responsible for the orange color of salmon or shrimp. This compound has been used in several studies showing a broad range of biological functions while most abundant reports are on its anti-inflammatory properties. Besides reports in animals, mainly mice, also some trials and reports in humans have been published. As a natural compound, the safety profile seems to be quite good while, so far, it is not clear how Astaxanthin works on a molecular level.
Animals in the ITP lifespan study have been treated with the compound from 12 months of age onwards. In a recently published paper, a median lifespan increase of 12% in male mice was reported while females did not show significant effects on lifespan. The results are currently further validated because the ITP started treatment groups at 11 and 16 months of age and at a different dose in 2022. We are keen to see more data on Astaxanthin in animals as well as in human clinical trials to validate its efficacy.
Astaxanthin’s Application in Humans:
So far Astaxanthin has not been approved in humans as a medical product but rather it is currently sold as a supplement. Nevertheless, numerous clinical trials are currently ongoing to validate the potential beneficial effects of this natural compound. Given the evidence of anti-inflammatory properties, it is used in studies targeting osteoarthritis and other inflammatory conditions as well as metabolic disorders.
Meclizine
The drug Meclizine is a first generation antihistamine that is currently still being used to treat motion sickness. Due to its ability to cross the blood-brain barrier, it can mediate effects on the central nervous system which also include side effects such as drowsiness or tiredness. There is a large body of literature on the use of meclizine in animal studies as well as human clinical trials.
Within the ITP lifespan studies this drug was tested in animals at 12 months of age showing a 15% of median lifespan increase in male mice while females were unaffected. Similar to Astaxanthin, this compound was tested in older animals and in a different dose in 2022. The latter results are still pending and are likewise excited to see more data given the compound’s huge clinical database.
Meclizine’s application in Humans:
Meclizine is currently being used to treat nausea, vomiting, and dizziness as the result of motion sickness. Also, it is used to treat vertigo caused by diseases affecting the inner ear. However, it is off market in Germany and some other countries in Europe. The number of clinical trials using meclizine is limited. Recent research points towards new pharmacodynamic effects of meclizine that might open up new possibilities for this drug in the future.
Experiments and Molecules Which Failed in the ITP
The ITP history has seen many more failures than successes, and that includes some “celebrity molecules.”
- Resveratrol is a molecule found in red wine and several other types of food. It briefly became a poster child for geroscience after a paper published in Nature in 2006 by Harvard professor David Sinclair showed that resveratrol increases lifespan in mice. Later studies, however, largely failed to reproduce those results. Rather than retell the whole saga which included the acquisition by Glaxo-Smith-Kline of Sinclair’s start-up for $600 million and its subsequent shutdown, let’s just say that currently, resveratrol is not topping the list of prospective anti-aging molecules, and its failures in ITP trials (it was actually tested in three dosages) did not improve its reputation.
- Another major fiasco took the longevity field by surprise: metformin, an anti-diabetic drug that showed strong promise in humans, failed ITP trials miserably. Metformin’s fame is based on solid research in humans, including one authoritative study that showed that people with diabetes who took metformin lived longer than regular healthy people. We do not know why metformin proved ineffective in the ITP, but scientists are not ready to give up on it. The failure, they say, can be attributed to dosage issues, differences between mouse and human biology, or other currently unknown factors. It is worth noting that a combination of metformin and rapamycin produced a synergistic effect on lifespan. Many scientists think that combination treatments are the future of longevity medicine.
- The third high-profile failure involved nicotinamide riboside (NR), a precursor to nicotinamide adenine dinucleotide (NAD), a ubiquitous molecule that mediates energy production in cells. The failure of NR was unanticipated, as NAD supplementation has been shown to improve many aspects of aging and age-related diseases in various model organisms. The reasons are unclear in this case as well, but, importantly, scientists did not detect elevated levels of NAD in tissues following the NR treatment — hence, this probably was a delivery issue. NR is not the only precursor to NAD, there is also nicotinamide mononucleotide (NMN), which is known to increase NAD levels in animal models. So, NMN might actually prove to be a better source of NAD for humans. The molecule has already become a popular supplement, though we would hold that more research is needed.
- The recent ITP Paper published a fairly famous failure: The compound Fisetin did not show any lifespan benefit using the established treatment protocol based in cohorts commencing with treatment in 2018 and 2019. Fiestin is intended to treat senescence. Cellular senescence is a state in which cells can enter once they reach their end of life which is, besides other properties, described by their resistance to normal cell death. These cells stay alive and are metabolically active by spreading their aged phenotype around in the surrounding cellular environment. During aging senescent cells tend to accumulate in the organism which is seen by a lot of researchers as one major aspect of aging. The clearance of senescent cells is one approach to reducing the speed of aging or even reversing age-related phenotypes. There is a lot of literature on senolytic compounds (those that can kill senescent cells) — Fisetin being one of them. Also, several human clinical trials are planned or ongoing to hopefully determine potential efficacy in humans. The failure of Fisetin to extend mouse lifespan can be seen as a surprise although there are several reasons for this. Future research will be needed to further evaluate the role of senolytic compounds in aging and age-related diseases
Things We Are Excited About
There are plenty of molecules that could possibly affect aging, and the current boom in geroscience keeps producing new candidates all the time. We believe that we should be proactive about these possibilities, identifying potential even before the drug is tested in humans. Here are some compounds that keep us on our toes.
Astaxanthin
Astaxanthin is currently in ITP trials and given the preliminary data it seems to have a positive effect on median lifespan in male mice. This molecule is a member of the vast carotenoid family. Carotenoids are pigments that give food its red and orange color. Astaxanthin is produced by algae and gives salmon its pink-reddish hue. Carotenoids have been associated with many health benefits and lower epigenetic age. Astaxanthin is a potent antioxidant and a modulator of several proteins that are important in the context of aging including FOXO3, Nrf2, Sirt1 and Klotho. Recent research has shown that astaxanthin might even delay brain aging. Given encouraging preliminary data and astaxanthin’s multi-prong action, we are bullish about this molecule.
Glycine
Arguably the most successful strategy for prolonging lifespan in model organisms has been dietary restriction in its various forms. It all began with caloric restriction (CR) which means simply consuming less calories. Drastic CR produced great results in rats back in the 1950s, giving a serious push to geroscience. Experiments with drastic (about 30%) CR in humans have been scarce, and, obviously, this is not the most comfortable way to live longer. Caloric restriction to this extreme may also create various health problems, including weakening of the immune system. This might be a lesser issue for animals living in lab conditions but could pose a serious risk for a “free range” human.
Instead, scientists have been devising more nuanced approaches. Many geroprotective drugs are thought to mimic CR. Intermittent fasting has been shown to recapitulate many benefits of CR, as well as protein restriction and amino acid restriction. In one important study, restricting the amino acid methionine in food led to a dramatic 42% increase in mean and 44% increase in maximum lifespan in rats.
Another amino acid, glycine, can clear excess methionine from the liver. One study showed that glycine supplementation mimics methionine restriction and extends lifespan in rats. These results got glycine into the ITP, where it produced a modest, but statistically significant effect on lifespan (median lifespan extension of 4% for females and 6% for males, maximum lifespan extension of 2% for females and 6% for males).
Methionine restriction also works by increasing the blood levels of glutathione. While supplementing glutathione directly has been a challenging task, glycine-based combinations may be the way to go, though more research is needed here. We also like glycine because, apart from rapamycin, it was the only drug in ITP studies that worked well for both sexes. While glycine’s results in the ITP were not as big as with other successful drugs, we still find them very intriguing and continue to follow this supplement closely. More research is needed though to understand the connection between methionine and glycine, but also what actually causes the positive effects of methionine restriction.
Spermidine
Spermidine has an impressive ability to induce autophagy — the process of breaking down and removing various cellular junk, such as dysfunctional organelles and misfolded proteins. Age-related decline in autophagy is thought to be a major cause of aging, and impaired autophagy correlates with shorter lifespan, as well as to more than a hundred diseases.
Spermidine has been linked by population studies to various health benefits in humans. It has also increased lifespan in animal models, including mice (about 10% increase in median lifespan). However, this study was small in size and run not by the ITP, but in a lab associated with a company that sells spermidine, so we would love to see data from more robust trials, also outside of this lab, to be fully convinced. Nevertheless, we absolutely believe in autophagy as an intervention target, which is why we started our company Samsara Therapeutics.
More Good Things to Come
Due to new discoveries, improvements in technology and increases in funding, new candidate life-prolonging drugs are being proposed at a mind-blowing pace. Testing them remains a challenge, but numerous advances are happening on this front as well. We are excited to be at the cutting edge of geroscience, watching things closely and making swift and informed investment decisions.
*This article does not intend to give any medical advice to readers or anyone else. This article is an opinion piece of members of the Apollo Health Ventures giving an overview of certain and herein indicated external studies which have not independently been validated by Apollo Health Ventures.
