Fight Aging!

In the open access paper I'll point out today, João Pedro de Magalhães, a long-standing member of both the transhumanist and aging research communities, casts an unbiased eye over present commercial efforts to treat aging as a medical condition, to slow or reverse its effects. The small online transhumanist community that blossomed with the advent of the web over the course of the 1990s includes many alumni who went on to join the scientific community, found biotechnology companies, write books, become advocates, or in other ways influence the course of today's world, now on the cusp of building rejuvenation therapies. Discussions of radical life extension, technological acceleration, and artificial general intelligence were far more fringe concerns back then than is now the case, but this growth in awareness isn't a coincidence. Visions slowly become reality because people work to make that happen. Technological progress is not accidental: it is led by our desires.

I should say that de Magalhães is here generous in not passing judgement on the value (or lack thereof) of most of the various ventures and classes of approach he surveys. But some approaches are definitely better than others, and to my eyes one the principal challenges at this time is to ensure that the effective (damage repair to reverse aging) rather than ineffective (metabolic alteration to slow aging) lines of research obtain significant support and funding. I think that there is definitely the need for some kind of metric to assess the utility of various efforts to address aging. Given figures for investment in a field, number of life span studies in various species, and average size of effect, one could potentially construct an Effectiveness Score to distinguish between fields that are absorbing a great deal of funding to no effect versus those that are more promising. I'd want an algorithm that clearly differentiates between, say, pharmaceutical targeting of mTOR, development of calorie restriction mimetics as a whole, and senolytics in terms of cost-effectiveness. I would expect the latter to be far more cost effective based on present data and the time and funding required to obtain that data. Sadly I suspect that no-one in the field has much of an incentive to participate in such an assessment, and obtaining the funding numbers wouldn't be an easy task.

The Business of Anti-Aging Science

The dream of fending off old age is as old as human civilization. Given the global aging of the population, developing interventions that preserve health in old age and postpone the onset of age-related diseases is more important than ever. In addition, we now know that it is possible to retard aging in animal models. Various genetic, dietary, and pharmacological interventions have been shown to increase lifespan, in some cases dramatically (tenfold is the current record), in short-lived model organisms like yeast, worms, flies, killifish, mice, and rats. Importantly, life-extending interventions not only increase longevity but can retard the onset of age-related diseases, resulting in the extension of healthspan (i.e., the length of time one lives in good health). These breakthroughs in the biology of aging and its impact on health and disease, referred to by some as 'geroscience', have led to the promise that we will be able to delay or slow human aging, resulting in unprecedented health benefits.

Leading causes of death worldwide, and notably in industrialized countries, are age-related diseases like cardiovascular diseases, cancer, and neurodegenerative diseases. Because of the strong relationship between the aging process and age-related diseases, the benefits emerging from anti-aging science have enormous potential. Using a model of future health and spending in the USA, the effect of delayed aging resulting in 2.2 years additional life expectancy would yield US$7 trillion in savings over 50 years; whereas addressing single pathologies such as cancer and heart disease would yield less, mostly due to competing risks. Given its huge potential financial benefits, anti-aging science has tremendous commercial opportunities. The anti-aging industry has struggled in the past in terms of reputation, but driven by more recent scientific breakthroughs it has been growing substantially with several young companies supported by world-leading brands.

As with most diseases, traditional pharmacological approaches are the most straightforward and widely explored way to target aging. Notable examples of anti-aging drug discovery efforts include pharmacological manipulations of sirtuins, sirtuin 1 (SIRT1) in particular (targeted by resveratrol), and TOR (targeted by rapamycin), which are currently being explored. TOR inhibition by rapamycin results in increased lifespan from yeast to mammals. In a small but groundbreaking clinical trial by Novartis, rapamycin improved immune function in elderly volunteers. Because rapamycin has various side effects, companies and laboratories are trying to develop safer analogs, known as 'rapalogs'. Research on resveratrol and sirtuins was high profile in 2008 when GlaxoSmithKline (GSK) purchased the sirtuin-focused biotech company Sirtris (based on work at Harvard Medical School) for US$720 million. Enthusiasm for resveratrol and sirtuins as anti-aging compounds has arguably declined in more recent years. Briefly, results have been largely disappointing since then. While Sirtris demonstrated that anti-aging biotech companies could rapidly grow in value and become a financial success for founders and early investors, its more recent problems might have hurt subsequent anti-aging science-based enterprises by discouraging investors and entrepreneurs.

Antioxidants have been historically a major focus of the field. However, currently the idea that antioxidant pathways play a major role in aging is being challenged, and epidemiological studies have largely failed to support the supposed benefits of antioxidants. While many dietary supplements still focus on antioxidants, few companies in the field maintain such a focus.

Telomeres, the protein-bound structures at the ends of chromosomes, shorten with cell division and, at least in some tissues, with age. Although genetic manipulations of telomerase in mice have yielded conflicting results, one study found that overexpression of telomerase in adult mice led to a 24% increase in median lifespan while not increasing the incidence of cancer. Therefore, the idea of activating telomerase as anti-aging remains a powerful one, even resulting in one self-experiment using gene therapy by BioViva.

Telomere shortening, as well as various stressors, can cause proliferating cells to stop dividing and enter a proinflammatory senescent state. There is evidence that senescent cells accumulate with age, at least in some tissues. In a landmark study, drug-induced clearance of p16Ink4a-positive cells (a marker of senescence) once per week from age 1 year extended the median lifespan in two normal strains of mice by 24-27%. Tumorigenesis and age-related deterioration of heart and kidney were delayed or slowed. As a consequence, Unity Biotechnology, a company founded by researchers at the Mayo Clinic involved in the above-mentioned work as well as the Buck Institute, has raised US$116 million from investors to develop senolytic (i.e., an agent that destroys senescent cells) treatments. Continuing research by the cofounders has focused on senolytic agents, including the killing of senescent fibroblasts with piperlongumine and ABT-263. Interestingly, they have also acquired a patent related to a senescent cell antibody for imaging and delivery of therapeutic agents.

Other companies focusing on senolytics include Oisin Biotechnologies, although, according to their website, they seem to be developing a genetically targeted intervention to clear senescent cells, suggesting a different approach than Unity. Moreover, Everon Biosciences has shown that a significant portion of cells with p16Ink4a expression may be a subclass of macrophage termed senescent associated macrophages (SAMs). Following this discovery Everon has announced that they will focus on these SAMolytic agents. Last, Siwa Therapeutics' focuses on developing antibodies against senescent cell markers capable of identifying and removing senescent cells.

With a decidedly Silicon Valley-based confidence, venture-capital funded big-data approaches are being pursued in aging and longevity science. High-profile players include Calico and Human Longevity Incorporated (HLI). Started as one of Google's moonshot projects in 2013, Calico is attempting to harness big data to improve understanding of the basic biology that controls lifespan. Not much is known about how this will look in practice. HLI is focused more directly on data than Calico and aims to create the largest database of integrated high-throughput assays - genotype, transcript, and microbiome data - along with deep phenotypic data on patients to fully map genotype to phenotype to inform health care in general. Published efforts have focused on deep sequencing of human genomes. Other companies are using big-data techniques to find new uses for already approved drugs. For one project Insilico Medicine uses deep learning on multiple 'omics' data types to find new relationships between existing drugs and gene regulatory pathways effected in, or otherwise related to, aging-related diseases.

In addition to reasons for spending on basic research in general, anti-aging science has unusual potential to benefit from market forces due to particularly favorable demographics. The median wealth of US families aged 62 years or older is over US$200,000, compared with US$100,000 and US$14,000 for middle-aged and young families, respectively. This may in part be responsible for the increase in investment in even non-traditional therapies and direct to consumer (DTC) products and services aimed at extending healthy lifespan. One high-profile DTC company is Elysium Health, which sells its Basis pill directly to consumers. Basis contains an NAD+ precursor, nicotinamide riboside, that declines with age and is required for sirtuin activity. Elysium has already concluded a preregistered, 2-month randomized, double-blind Phase I trial for Basis using 120 healthy 60-80-year-olds. While results have yet to be published, a company press release claims that participant's blood NAD+ levels were increased by 40% for the duration of the second month. However, the release did not mention the results for health measures.

Caloric restriction (CR) is the most studied and most consistent intervention that increases both health- and lifespan. While a CR diet is too harsh for most people, intermittent fasting (IF) has been proposed as a less-restrictive alternative. Based on this premise, L-Nutra was created to develop and market proprietary fasting-mimetic meals designed to provide the beneficial effects of IF.

A growing number of companies are now focusing on anti-aging science. In a way this is surprising, given that the first high-profile anti-aging company, Sirtris, while a success as an early investment has thus far failed to live up to its anti-aging expectations. Modern advances, abundant aging-related targets and an aging population can arguably be driving the current crop of anti-aging biotechs, but how realistic is it that these will succeed? In a sense there are few assumptions of which we can be confident. At present we can state that: (i) aging is a complex process; (ii) although there are numerous theories of aging with vocal advocates, there is no consensus among scientists regarding the underlying causes of aging; and (iii) aging can be manipulated in short-lived model systems by genetic, dietary, and pharmacological intervention. However, that leaves many open questions, so the uncertainty concerning human anti-aging approaches remains very high.

Although findings from short-lived model organisms, particularly in terms of the plasticity of aging, have been a major breakthrough in the field, the degree to which they are relevant to humans is unknown. Human homologs of genes associated with aging in model organisms have been associated with human longevity in some cases, but these are rare and thus our understanding of the genetic basis of human longevity remains largely unknown. Therefore, it is plausible that most findings from short-lived model organisms will not be relevant to human beings. Briefly, not only may the pathways necessary to extend lifespan in model systems be often irrelevant to the comparatively long-lived human species. Given the above concerns, a major open question is how effective anti-aging interventions can be in humans. Even if they have benefits, how do these compare with mundane lifestyle choices like going to the gym?

Of the 4000 private and 600 public biotech companies worldwide, only a few percent have shown increasing profitability. Historically, only one in 5000 discovery-stage drug candidates obtain approval and only a third of those recoup their R&D costs. Besides, the success rate of clinical trials is not improving, although we have more information, data, and potential targets than ever before. Given the various constraints on the study of aging, including the reliance on short-lived model organisms, long validation times, and poor biological understanding, it would be surprising if most of the companies described here are active a mere 5-10 years from now. Likewise, most companies in the anti-aging biotech sector are startups, and thus riskier. From an investor's perspective this means that investors in anti-aging biotech are expecting to lose money but hoping to win big.

Omics approaches are imperative, as is a multidisciplinary outlook, but while these have augmented the search space, attrition rates remain very high. Perhaps surprisingly, despite the so-far failure of Sirtris, which would be expected to hurt the industry, anti-aging biotech is more vibrant than ever. Clearly even such high-profile failure has not dissuaded investors, including many tech billionaires. No doubt new technologies will be developed and new targets discovered in the coming years and decades, possibly opening new avenues for the commercialization of aging in other directions. The promise of fending off old age remains more powerful than ever and the financial gains for any company delivering on that promise will continue to be extremely attractive. Anti-aging biotech can then be seen as an extreme reflection of the biotech sector: risky and most likely to fail, but if one company is successful the outcomes are monumental.