Anti-aging Science Has Unusual Potential To Benefit From Market Forces Due To Particularly Favorable Demographics

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Basic Biology and Big Data

With a decidedly Silicon Valley-based confidence inspired by the successes of the high-tech industry spanning four decades, venture-capital funded big-data approaches are being pursued in aging and longevity science. High-profile players include Calico and Human Longevity Incorporated (HL).

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Starting as one of Google's moonshot projects in 2013, Calico is attempting to harness big data to improve its understanding of the basic biology that controls lifespan. Not much is known about how this will look in practice; however, they have formed an up-to-US$1.5 billion partnership with AbbVie to develop drugs targeting diseases related to old age (https://news.abbvie.com/news/abbvie-and-calico-announce-novel-collaboration-to-accelerate-discovery-development-and-commercialization-new-therapies.htm). Another high-profile player is HLI by Craig Venter. sistanche 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. what is cistanche Published efforts have focused on the deep sequencing of human genomes [32]? Other companies are using big-data techniques to find new uses for already approved drugs [12]. This is an attractive approach as pharmaceutical companies incur US$1.8 billion in capitalized costs to develop and obtain approval for drugs from scratch, while the safety of approved drugs is already known [33]. While many companies do this, it forms a key component of some companies in longevity science. For one project Insilico Medicine uses deep learning on multiple 'omics' data types to find new relationships between existing drugs and gene regulatory pathways affected in, or otherwise related to, aging-related diseases. Chronos Therapeutics, by contrast, focuses on neurodegeneration-specific age-related diseases. They patented the use of fujimycin, an already FDA-approved immunosuppressive drug for the treatment of eczema and organ transplantation, to treat disorders related to cellular lifespan, which include many age-related diseases such as cardiovascular diseases, type 2 diabetes, Alzheimer's, and osteoporosis, by increasing cell lifespan through disruption of OBD1, a sirtuin inhibitor [34]. While these approaches remain unproved in terms of translation, it is interesting to note that a network pharmacology approach was recently shown to be able to predict new life-extending compounds in worms [35].

DTC Approaches

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 ofUS 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 DTC products and services aimed at extending a healthy lifespan.

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One high-profile DTC company is Elysium Health, which sells its Basis pill directly to consumers. Basis contains a NAD precursor, nicotinamide riboside, that declines with age and is required for sirtuin activity; it also contains pterostilbene, which is similar to resveratrol. The systemic decline of NAD plus with age is a possible cause of age-associated changes in sirtuin activity in both the nucleus and mitochondria, resulting in age-associated dysfunction and pathologies [36]. In addition to its role in redox reactions, NAD plus is an important substrate of several enzymes: sirtuins, ADP-ribose transferases, PARPs, and CD38/CD157 (cADPR synthases)[37.

Elysium has already concluded a preregistered,2-month randomized, double-blind Phaseltrial for Basis using 120healthy 60-80-year-olds. While results have yet to be published, the accompanying press release claims that participants' blood NADt levels were increased by 40 percent for the duration of the second month. However, the release did not mention the results for health measures such as lipid profile, physiological performance, or sleep quality (https://www. elysiumhealth.com/clinical-trial-press-release).

Box 2. Intermittent Fasting Is Less Restrictive Than Caloric Restriction

IF-where, for example, calories are reduced by 40 percent on 2 clays per week-has been argued by some experts to have the same range of benefits as chronic CR [63]. In a further refinement, a low-calorie/low-protein diet eaten for 4 days every 2 weeks, without affecting total long-term caloric intake, appears to have similar effects. Middle-aged mice showed improvements in a broad set of age-related phenotypes including reduced visceral fat, lower incidence of some cancers, fewer tissues with inflammation, reduced immunosenescence, improvement of some types of memory, and an 11 percent increase in median lifespan [40]. Anti aging cistanche A similar diet taken 5 days per month for 3 months resulted in reduced fasting glucose, lower circulating IGF1 level, fat loss, and reduced CRP in those with elevated cardiovascular disease risk in a 38-person preregistered pilot trial [40]. Subsequently, a similar pilot trial of 100 healthy participants reported a reduction in markers for aging, diabetes, cancer, and cardiovascular disease [64].

Another notable product, Juvenon, Juvenon, uses a-lipoic acid and acetyl-carnitine as the main ingredients. Feeding rats acetyl-l-carnitine and a-lipoic acid leads to a decline in oxidative stress and DNA damage as well as improved movement and memory [38,39]. 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 (Box 2). Based on this premise, L-Nutra was created to develop and market proprietary fasting-mimetic meals designed to provide the beneficial effects of IF. Their first formulation, FroLon, comprises 5 days of meals to be taken every 1-6 months. In a registered, randomized 38-person clinical trial, ProLon was shown to reduce weight and abdominal fat and maintain healthy levels of blood glucose, C-reactive protein (CRP), and insulin-like growth factor 1 (IGF1)[40].

Using long-lived 'Methuselah'flies, Genescient uses genetic and gene expression network analysis to discover the genetic determinants of this long-lived strain. Their goal is to translate these findings into human targets by developing nutrigenomics-based therapies for chronic age-related diseases. Their proprietary combination of four herbal extracts had mixed results in extending lifespan in flies, with a greater effect on stressed flies [41].

Young Blood

Perhaps most uniquely surprising, therapies are now being tested based on research into the effects of parabiosis (Box 3). A Stanford University spinout, Alkahest, with some of the main parabiosis researchers on board, was formed to take advantage of this research and test the effect of young plasma as a treatment for Alzheimer's. Grifols, the largest plasma-based manufacturer worldwide, has invested US$38 million in Alkahest with an additional US$13 million to develop and sell Alkehest's plasma-bassed products (http://www.grifols.com/en/web/international/view-news/-/new/grifols-to-make-a-major-equity-investment-in-alkahest). Additionally, young human blood has been shown to revitalize brain function in old mice [42]. One further company, Ambrosia, was established to run a clinical trial on the anti-aging benefits of young blood in relatively healthy people [25,43]. Controversially, however, the company is Box 3. Anti-Aging Effects of Young Blood In biology, parabiosis is the joining of two animals' circulatory systems. Historically it was noticed that connected healthy animals could extend the lifespan of treated animals [65], although such effects have not been subsequently validated. In a series of studies starting in 1950, it was observed that the older the pair exhibited better longevity and tissue function [65] whereas young mice exposed to old plasma showed a decrease [66]. Further, aged mice given young plasma showed improvement in age-related decline in hippocampus-dependent learning and memory [67]. cistanche benefícios However, 10-12-month-old CBA/Ca female mice (a strain with normal longevity) injected weekly with young plasma did not show increased lifespan [68]. Most recently, using a blood-exchange device to exchange blood between young and old mice once, old mice exhibited improved pathogenesis and response to muscle injury while young animals showed no difference in injury response and worsened hematogenesis. For every other test - including physical performance and hippocampal neurogenesis - while young mice worsened, old mice showed no difference [69]. planning to charge participants US$8000, making this a pay-to-participate trial that has raised ethical concerns [43].

Stem Cells and Regenerative Medicine

Several companies have also been focusing on stem cells and regenerative medicine. Given the multiple uses of stem cells, the applications in regenerative medicine extend far beyond aging conditions and diseases. Nonetheless, a few companies have focused in particular on age-related conditions. Examples include BioTime, which aims to develop embryonic/iPS stem cell therapies and regenerative medicine; Centagen, which aims to activate adult stem cells; and RepliCel Life Sciences, which focuses on regenerative medicine to treat injured tendons, pattern baldness, and skin damaged by sun and age.

Challenges in Developing Human Anti-Aging Therapies

A growing number of companies are now focusing on anti-aging science (Table 1).In a way, this is surprising, given that the first high-profile anti-aging company, Sirtris, while successful 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 a few assumptions of which we can be confident. At present we can state that:(i) aging is a complex process;() although there are numerous theories of aging with vocal advocates, there is no consensus among scientists regarding the underlying causes of aging; and (ii) 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.

Humans Are Not Huge Worms or Big Mice

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 (Figure 2) and thus our understanding of the genetic basis of human longevity remains largely unknown 44]. For example, one recent large-scale study found only two loci significantly associated with human longevity and failed to validate previous findings like the association of /GF1R with longevity [45]. Therefore, it is plausible that most findings from short-lived model organisms will not be relevant to human beings [44]. Briefly, not only may the pathways necessary to extend lifespan in model systems be often irrelevant to the comparatively long-lived human species,

Figure 2. Genetics of Aging from Model Organisms to Humans, The numbers below each organism represent the number of aging- and/or longevity-associated genes for each organism in build 18of the GenAge database [2]: for humans, only genes directly associated with human aging and/or longevity according to GenAge are included. The area of each circle is proportional to the number of genes.

but, to make matters worse, studies in model systems are mostly performed on genetically homogeneous laboratory strains that may not be representative of human populations [44]. Besides, our understanding of aging manipulations in short-lived models like yeast and worms is far superior to that in rodents [1,2,46] due to the ease of performing large-scale screens (Figure 2).

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? Likewise, while some anti-aging therapies might have benefits, they may not be beneficial for everyone. On the bright side. there are various efforts to develop alternative model systems, including dogs [47| and primates [48], although of course, the limitation is that studies in such animals take much longer and are more expensive than in rodents.

So Many Targets, So Little Time

According to the GenAge database, we now know of >2000 genes that modulate longevity in model organisms [2], and the drug database lists >400 compounds that can increase longevity in model organisms [46]. Most aging-related genes and pathways have not yet been targeted pharmacologically [46]. Given the volumes of data generated in the life sciences, various approaches in computational and systems biology have been developed to help identify and rank new candidates, identify regulatory genes, and gather biological insights [35,49-51], as reviewed in [52]. Such approaches are imperative, as is the integration of differing expertise in developing and prioritizing targets, drugs, and therapies for testing. Despite these advances, our capacity to identify interventions that will succeed in clinical trials remains poor.

One crucial limitation in biotech is the long time it takes for clinical validation and to obtain regulatory approval [53]. Taking several years, clinical trials are long, expensive operations. In aging, this is even more of an issue because aging is, compared with traditional diseases, a relatively long process, and we still lack accepted aging biomarkers that can be used as endpoints. In addition, the field of life sciences remains immature in that our knowledge of human biology is still veryincomplete[54]. Thus, while the number of targets has increased dramatically thanks to advances in technologies like genomics, our capacity to validate those targets in a clinical setting has not substantially improved [53]. In other words, the success rates of clinical trials remain very low [55], and pharmaceutical R&D efficiency has even declined [56], despite what is generally agreed as substantial technological progress in recent decades. Therefore, biotech is a risky business that requires long-term involvement, and anti-aging biotech is even more sO.

Clinical Trials for Aging and Rejuvenation

Because of the time, it takes foraging to develop, clinical trials for aging per se are not realistic at present. One effort, however, is trying to perform the first clinical trial for aging, using metformin, which would be an important proof of principle [57]. Even if this is successful, there are many practical challenges in performing clinical trials for aging, including how long it will take and how much it will cost [1,58,59]. As mentioned above, we also still lack suitable biomarkers of aging, which is a major impediment [12]. Recent advances in the development of epigenetic biomarkers of aging-an 'epigenetic clock'-offer promise [60] but it remains unclear whether these are suitable for clinical trials.

An additional concern in anti-aging interventions is whether these are suitable for old and frail individuals and/or for long-term administration. Drugs like metformin already in clinical use may be particularly suitable for targeting aging, and recent discussions have explored how to develop a preclinical drug development pipeline in anti-aging [58,59]. In addition, while commercialization of medical interventions is dominated by small-molecule pharmaceuticals. investments

stemming from advances in anti-aging science now include young blood therapies, senescent cell ablation, and DTC diets and nutraceuticals(Table 1).

One important development in anti-aging therapies focuses on rejuvenation. Some anti-aging interventions like resveratrol and many longevity drugs promise to slow aging, which for clinical testing entails a variety of problems as described above. However, interventions like senolytic drugs and young blood promise rejuvenation, which is less challenging from a validation perspective and therefore much more attractive for commercial exploitation. Therefore, developing interventions that reverse at least some aspect of aging is a more powerful translational path than trying to slow aging.

Concluding Remarks and Future Prospects

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 [61]. Besides, as mentioned above, the success rate of clinical trials is not improving, although we have more information, data, and potential targets than ever before (see Outstanding Questions). 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. Cistanche Extract Anti Radiation 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 a 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.

This article is extracted from Trends in Biotechnology, November 2017, Vol. 35, No. 11 1071