TLDR: in the past decade longevity has emerged as a serious research field. There are now a number of studies that indicate that a number of safe supplements may likely extend lifespan and health in adult humans.

Note: I normally blog about statistics and machine learning. This article is different and I hope my readers will find the information interesting.

Healthy Ageing

"I would like to live long and in good health."

-- Approximately 99 percent of humans.

Modern societies enable us to live in good health. Investment into healthcare systems, emergency response, medical research, pharmaceutical industries, but also elderly care facilities, gyms and sports, as well as educational policies and taxes for products causing ill health such as alcohol and tobacco all lead to better health outcomes and longer lives. Even policies and politics that lead to world peace and lower violence have remarkable outcomes on longevity.

These efforts have been remarkably effective, and globally so: in 1900 the global average life expectancy at birth was just 31 years. In 2020 it is 72.6 years. The average increase per year in life expectancy globally between 2000 and 2020 has been 0.46 percent.

Despite this amazing progress, the idea of systematically aiming scientific research at directly extending lifespan or even to overcome death entirely is recent. Of course, the idea of living forever---to cheat death---is not new. In fact, it appears in the oldest surviving story. However, before the last decade most serious scientists did not consider it possible to overcome death; after all any empiricist can see that all humans eventually have to die. Yuval Harari puts this as follows:

"Even a few years ago, very few doctors or scientists would seriously say that they are trying to overcome old age and death. They would say no, I am trying to overcome this particular disease, whether it's tuberculosis or cancer or Alzheimers. Defeating disease and death, this is nonsense, this is science fiction."

--- Yuval Harari, in a 2015 interview with Daniel Kahnemann

Not only has the last decade changed the view of serious scientists, there are now organized efforts and serious funding. The SENS foundation, founded in 2009, has limited funding but coordinates a number of research programmes and investments in longevity startups. Calico, founded in 2013 as part of Google, has a mission to combat ageing and 2.5B USD investment. Juvenescence, a UK-based longevity startup secured 100M USD investment in 2019. There are many other smaller companies and institutional investors now regularly fund these startups. For investors it makes sense: not only is the total addressable market of longevity products all of humanity, but it also seems that a technical solution to death is in reach within our lifetime. Yuval Harari again puts it better than I could:

"People never die because the Angel of Death comes, they die because their heart stops pumping, or because an artery is clogged, or because cancerous cells are spreading in the liver or somewhere. These are all technical problems, and in essence, they should have some technical solution. And this way of thinking is now becoming very dominant in scientific circles, and also among the ultra-rich who have come to understand that, wait a minute, something is happening here. For the first time in history, if I'm rich enough, maybe I don't have to die."

--- Yuval Harari, in the same 2015 interview

In parallel to these more visible investments and research efforts, there is also a renewed interest in the study of ageing-related effects in existing medication and nutritional supplements. In the remainder of this post we will look at some of the safer supplements and what we now know about them.

But first, a disclaimer.

Disclaimer: This article is not a substitute for consulting your physician about which supplements may or may not be right for you. I do not endorse supplement use or any product or supplement vendor, and all descriptions here are for scientific interest. Also: I am not a medical doctor or physician.

With the disclaimer out of the way, lets start.

Alpha-Ketoglutarate (AKG)

• Supplement name: Arginine Alpha-Ketoglutarate (AAKG)
• Typical supplement dosage: 2000 mg/day
• Typical supplement price: 0.35 USD/day

Alpha-Ketoglutarate is naturally present in human blood plasma and is part of the metabolic cycle. However, naturally occuring AKG levels decrease severely with age, with a ten-fold reduction between the age of 40 and 80 years. As a supplement AKG has an excellent safety record and is widely and freely available, commonly used in the bodybuilding community. Two reviews on what is known about the effects on AKG in the human body are (Wu et al., Biomol Ther, 2016) and (Liu et al., BioMed Research International, 2018).

AKG was first identified as a possible longevity supplement in the nematode C. elegans animal model, (Chin et al., Nature 2014), (free PDF). In that study the authors demonstrated a concentration-dependent improvement of lifespan, achieving an almost 50 percent increase in lifespan and delaying age-related diseases. Moreover, Chin et al. identified one causal mechanism for these benefits.

(Shahmirzadi et al., Cell, 2020), (preprint PDF) report on a study done in mice. They demonstrate robust improvements in lifespan and healthspan when supplementing the mouse diet with AKG, with lifespan increased by about 10 percent (slightly more for female mice, slightly less for male mice). In particular, the AKG supplementation postpones the occurence of a number of aging phenotypes such as deterioration of color in the fur and weakened grip strength of the mice, and improvements are also present when only starting AKG supplementation in the later half of the mouse's life.

The study concludes:

"Given its GRAS status and human safety record, our findings point to a potential safe human intervention that may impact important elements of aging and improve quality of life in the elderly population."

--- Shahmirzadi et al., 2020

Glucosamine Sulphate

• Supplement name: Glucosamine Sulphate
• Typical supplement dosage: 1500 mg/day
• Typical supplement price: 0.10 USD/day

Glucosamine is a supplement commonly used to manage joint pain as it has been shown to be able to relieve joint pain. A recent study (Ma et al., BMJ, 2019) based on large sample observational UK Biobank data showed that regular use of glucosamine supplements is associated with lowering the risk of cardiovascular disease. Another recent study, (Li et al., Annals of the Rheumatic Diseases, 2020), also based on large sample observational UK Biobank data (\(n=495,077\)) finds compelling evidence that Glucosamine may lead to overall reduced mortality. While Li et al. do not perform a randomized controlled trial and hence such observational data does not imply causation, they do consider confounders and perform a detailed analysis on large sample subgroups. They carefully note:

"In general, with the current observational study design the possibility of residual confounding due to imprecise measurements or unknown factors cannot be excluded for all findings in our study, despite our careful adjustment of all measured confounders."

However, the effect size in Li's study is large: assuming an absence of non-measured confounders, the hazard ratio for a nine year follow-up period for overall mortality is 0.85 with regular glucosamine supplementation, meaning that there is a 15 percent less death compared to the non-glucosamine supplemented group. For cardiovascular mortality, respiratory mortality, and digestive mortality the hazard ratio is even stronger at 0.82, 0.73, and 0.74, respectively. The authors conclude that

"regular glucosamine supplementation was associated with lower mortality due to all causes, cancer, CVD, respiratory and digestive diseases."

Glucosamine supplementation is considered safe by the US National Center for Complementary and Integrative Health and no side effects are known when used regularly for multiple years.

NAD+ boosters: NMN / NR

• Supplement name: Nicotinamide riboside chloride (NR)
• Typical supplement dosage: 300-1000mg NR (sold as "TRU NIAGEN"), taken in the morning on an empty stomach
• Typical supplement price: 1.80 USD/day (300mg dose)

and

• Supplement name: Nicotinamide mononucleotide (NMN)
• Typical supplement dosage: 500-2000mg MNM, taken in the morning on an empty stomach
• Typical supplement price: 0.34 USD/day (500mg dose)

NAD+, nicotinamide adenine dinucleotide, is central to metabolism in many organisms, including humans. NAD+ levels decrease strongly with age, (Massudi et al., PLoS ONE, 2012). The reasons for this decline is not yet fully understood but is actively researched, (Schultz and Sinclair, Cell Metabolism, 2017).

While NAD+ decreases with age, does the low NAD+ level cause aspects of ageing? Schultz and Sinclair put this poetically,

"The discovery of nicotinamide adenine dinucleotide (NAD+) as a "cozymase" factor in fermentation has its 110th anniversary this year [2016]. Of the two billion people who were alive back in 1906, only 150 people remain. Interestingly, NAD+ itself may be the reason for their longevity."

--- Schultz and Sinclair, 2017

A growing line of research in the last 15 years proposes to artificially elevate NAD+ levels to improve health in ageing individuals. For a number of reasons NAD+ cannot be directly used as supplement. Instead a number of precursors are used. Two of these, NR and NMN, have been shown to lead to dose-dependent increase of bioavailable NAD+ in humans, (Trammell et al., Nature Communications, 2016), and (Poddar et al., 2019). NR is a vitamer of Vitamin B3 and present in normal human diet. Likewise NMN is found naturally in small amounts in some foods such as broccoli and avocado.

In an important paper, (Zhang et al., Science, 2016), NR supplementation has extended lifespan in mice by 10 percent. In particular, NR supplementation has direct observable effects on markers of ageing such as muscle function. The authors conclude that:

"Our findings suggest that NAD+ repletion may be revealed as an attractive strategy for lengthening mammalian life span."

--- Zhang et al., 2016

There is now strong causal evidence that NAD+ supplementation in the form of NMN or NR has health and ageing benefits in mice through a broad set of mechanisms, (Yoshino et al., Cell Metabolism, 2018), (Poddar et al., 2019). Recently NAD+ supplementation via NMN has even been shown to restore female fertility in ageing mice, (Bertoldo et al., Cell Reports, 2020).

For both NR and NMN there are no large scale studies in humans. A small scale study on NR in human adults, (Martens et al., Nature Communications, 2018) showed some cardiovascular benefits but the small scale of the study makes conclusions difficult.

The safety of NMN and NR is only partially established. Both occur naturally in a normal human diet but only in small amounts, much smaller than the amount used in supplements. NR is generally recognized as safe and a randomized controlled human trial study, (Conze et al., Nature scientific reports, 2019), finds no adverse effects over a duration of eight weeks. In comparison NMN has limited safety studies, (Irie et al., 2019). However, for both NMN and NR there are is no long-term safety data available for humans.

Overall NMN and NR supplementation are promising supplements to improve healthspan in humans, but a definite conclusion is still open. Definite results will likely be available within the next ten years. In practical terms one big disadvantage at the moment is that NR is comparatively expensive.

Resveratrol

• Supplement name: Resveratrol
• Typical supplement dosage: 500-1000 mg/day
• Typical supplement price: 0.15-0.30 USD/day

Resveratrol is a substance naturally occuring in plants in low concentrations. In food one of the highest concentrations of resveratrol is present in red wine, however, even the highest concentrations occuring naturally in food (up to 15mg per liter) are well below doses used when using resveratrol as supplement.

There is a wide body of evidence that supplementation with resveratrol has strong beneficial health effects in a wide variety of animals. A comprehensive review article, (Baur and Sinclair, Nature Reviews, 2006), summarizes the state of knowledge around 2006:

"Resveratrol, a constituent of red wine, has long been suspected to have cardioprotective effects. Interest in this compound has been renewed in recent years, first from its identification as a chemopreventive agent for skin cancer, and subsequently from reports that it activates sirtuin deacetylases and extends the lifespans of lower organisms. Despite scepticism concerning its bioavailability, a growing body of in vivo evidence indicates that resveratrol has protective effects in rodent models of stress and disease."

--- Baur and Sinclair, 2006

Most importantly at that time there already was evidence of lifespan and healthspan extension by resveratrol:

• Yeast, 70 percent mean lifespan extension;
• Nematode Caenorhabditis elegans, 18 percent mean lifespan extension;
• Fly Drosophila melanogaster, 29 percent mean lifespan extension;
• Turquoise killifish Nothobranchius furzeri, 56 percent mean lifespan extension.

While these are very different animals and the lifespan extension varies, the effect size is nevertheless remarkably strong. In 2006, Baur and Sinclair state:

"The question of whether enhanced SIRT1 activity and/or resveratrol treatment will increase mammalian lifespan looms large in the ageing-research community. (...) It is becoming clear that resveratrol and more potent mimetics show great promise in the treatment of the leading causes of morbidity and mortality in the Western world. So far, little evidence suggests that these health benefits are coupled with deleterious side effects. Even the trade off between individual health and reproductive potential that is characteristic of caloric restriction does not seem to occur in animals with lifespans that have been extended by resveratrol. Could resveratrol and similar molecules form the next class of wonder-drugs?"

--- Baur and Sinclair, 2006

A first study on mammals in the form of mice was also published by the same authors in 2006, (Baur et al., Nature, 2006). It demonstrated no lifespan extension by resveratrol supplementation but convincingly demonstrated that mice that are fed on a high calorie diet together with resveratrol survive as well as normally fed mice and have similar health characteristics, whereas mice fed the same high calorie diet without resveratrol suffers adverse health and shortened lifespan. Interestingly the mice fed with the high calorie diet and resveratrol were healthier but had the same body weight as the mice that only received the high calorie diet.

A result similar to the "high calorie diet" study on mice was repeated on humans: (Timmers at al., Cell Metabolism, 2011) report broad improvements of health markers on obese humans supplemented with resveratrol. The authors conclude,

"In conclusion, we demonstrate beneficial effects of resveratrol supplementation for 30 days on the metabolic profile in healthy obese males, which seems to reflect effects observed during calorie restriction. Although most of the effects that we observed were modest, they were very consistently pointing toward beneficial metabolic adaptations. Furthermore, therewere no effects on safety parameters, and no adverse events were reported."

--- Timmers et al., 2011

Given these promising findings on health benefits, what about lifespan extension in mammals and humans? A meta-analysis across studies with different species, (Hector et al., Biological Letters, 2012) could confirm the life extension effect of resveratrol but found a diminished effect for higher-order species.

(Pearson et al., Cell Metabolism, 2008) perform a study on mice that demonstrates no increase in lifespan for normally fed mice that received resveratrol supplements. But again these mice showed a marked improvement in health markers when compared to mice that did not receive resveratrol:

• Significantly improved bone density at age;
• Reduction in age-related cataracts at age;
• Improved balance and motor coordination at age; and
• Improved cardiovascular function at age.

The observed health benefits are similar to those of a low calorie diet, which has been shown to lead to both increased healthspan as well as lifespan extensions in mammals, (Pifferi and Aujard, 2019). However, here only health is improved, not lifespan.

The authors conclude:

"In conclusion, long-term resveratrol treatment of mice can mimic transcriptional changes induced by dietary restriction and allow them to live healthier, more vigorous lives. In addition to improving insulin sensitivity and increasing survival in HC mice [high calorie diet mice], we show that resveratrol improves cardiovascular function, bone density, and motor coordination, and delays cataracts, even in nonobese rodents. Together, these findings confirm the feasibility of finding an orally available DR [dietary restriction] mimetic. Since cardiovascular disease is a major cause of age-related morbidity and mortality in humans but not mice, it is possible that DR mimetics such as resveratrol could have a greater impact on humans. However, resveratrol does not seem to mimic all of the salutary effects of DR [dietary restriction] in that its introduction into the diet of normal 1-year-old mice did not increase longevity."

--- Pearson et al., 2008

Overall, the available evidence makes it likely that humans will also enjoy some health benefits at age when regularly using resveratrol supplementation. Whether resveratrol supplementation also has longevity benefits in humans is an open question.

Safety: a metastudy of clinical trials of resveratrol, (Patel et al., Annals of the New York Academy of Sciences, 2011), analyzed the data of 17 studies of resveratrol in humans and found no adverse effects for typical doses up to 1g per day in humans and minor dose-dependent side effects for doses up to 5g per day.

Multivitamin Supplementation

• Supplement name: generic multivitamin supplement
• Typical supplement dosage: typically 1 pill/day with dosages matching US FDA recommendations
• Typical supplement price: 0.10 USD/day

General multivitamin supplements are widely available and widely used. A recent study finds that users of multivitamins often self-report better health status than clinically present, see (Paranjpe et al., 2020). In addition the study finds that no clinical differences exist between people using multivitamin supplements and people who do not.

However, vitamin deficiency is a real thing and multivitamin supplements are safe, cheap, and effectively guard against certain deficiencies.

Take vitamin D deficiency for example: (Forrest and Stuhldreher, Nutrition Research, 2011) report that 41.6 percent of US adults have a vitamin D deficiency (higher depending on skin type, with a vitamin D deficiency present in 82.1 percent of blacks, and in 69.2 percent of Hispanics). They conclude:

"Given that vitamin D deficiency is linked to some of the important risk factors of leading causes of death in the United States, it is important that health professionals are aware of this connection and offer dietary and other intervention strategies to correct vitamin D deficiency, especially in minority groups."

--- Forrest and Stuhldreher, 2011

Take vitamin B deficiency for example: (Sechi et al., Nutrition Reviews, 2016) summarize multiple studies of empirically observed vitamin B deficiencies in different populations. For elderly persons (age 65 and up) vitamin B deficiency is observed at 22.9 percent for vitamin B1, 11.7 percent for vitamin B2, and 30 percent for vitamin B9. They also report on the potential neurological impairments that come with vitamin B deficiencies and while they do not advocate for broad supplementation they conclude:

"Taken together, these findings indicate that subclinical or overt B vitamin deficiency, with frequent involvement both of the central and peripheral nervous system at all stages of life, is a global health concern, especially in selected populations at risk and in certain clinical settings."

--- Sechi et al., 2016

So overall, while you will likely not benefit from multivitamin supplementation if you have a varied diet and an active lifestyle, it is still cheap and safe and provides an additional guard against certain vitamin deficiencies which can have real health consequences.

Summary

In the last 15 years scientists have identified a number of promising supplements that yield health benefits and potentially increase lifespan. Should we all take these supplements then? Given the partial evidence we always have to make an uncertain risk/benefit tradeoff, the main risks being the known side effects and the unknown potential long-term consequences.

The potential benefits of healthspan and lifespan extension are large and we are objectively at the dawn of a revolution in our understanding of ageing and in treating ageing. We should not be surprised if any of the above supplements prove their promise in human studies within the next decade.

Not included

I intentionally did not include medications and certain supplements:

• Creatine: generally a beneficial supplement for muscular function. It has been studied for possible beneficial effects on aging, but it is too early to tell, see (Smith et al., 2015).
• Metformin: a prescription medicine used for treating diabetes. There is strong causal evidence of a link of Metformin to delaying ageing in mice, (Martin-Montalvo et al., Nature Comms, 2013), and strong evidence of a potential Metformin-related reduction of overall mortality in humans with effect size measured in years, (Campbell et al., Ageing Research Reviews, 2017), and potential link to reduction of dementia, (Campbell et al., Journal of Alzheimer's Disease, 2018). A recent summary of what we know about Metformin in ageing is (Piskovatska et al., Biogerontology, 2018). There are three reasons why I do not include Metformin in the above list: 1. Metform in a prescription medicine in most of the world, not a supplement; 2. while Metformin overall is relatively safe and has been used for decades to treat diabetes, there are very common and unpleasant side effects including diarrhoea, nausea, and vomiting; and 3. two large randomized controlled human trials evaluating Metformin specifically as a treatment for ageing are currently underway.
• Rapamycin: a prescription medicine that is an immunomodulator and has an overwhelming evidence base of increasing longevity and to enhance health markers in a wide variety of animals including mammals with large effect sizes. A randomized double-blind placebo-controlled study, the PEARL study, to be completed in December 2023 studies the anti-ageing effects of Rapamycin in 150 humans. For an opinionated but well-written overview of the primary literature, see (Blagosklonny, Aging, 2019).