Longevity genomics paper retracted

On July 22, 2011, a high-profile longevity genomics paper published in Science in July 2010 was retracted. The paper, ‘Genetic Signatures of Exceptional Longevity in Humans,’ was the work of Thomas Perls and Paola Sebastiani (Boston University). The initial study had been revised per editorial concerns that arose last year, but has now been retracted possibly due to issues related to the replicatability the findings.

The revised study results were presented by the team at the American Aging Association meeting in June 2011. These data featured nine single SNP associations (versus two previously), and linked 281 SNPs to signatures for exceptional longevity (versus 180 SNPs previously). The overall conclusion remained unchanged - that

centenarians, while having the same disease mutational profiles as non-centenarians, have other specific aspects to their genetic profiles which indicate a signature for exceptional longevity

Practical applications in anti-aging

One nice aspect of aging conferences is that there are usually a few gems of information that can be applied immediately in humans. Several actionable solutions were highlighted at the 40th annual meeting of the American Aging Association held June 3-6, 2011 in Raleigh NC USA (conference summary), in the areas of pharmaceuticals, nutrition, lifestyle, exercise, and fasting.

In summary, hypertension drug losartan may help sarcopenia, the healthier fats and antioxidants in walnuts, blueberries, and nectarines may facilitate health, hot tubs may reduce blood pressure, endurance exercise is better for older adults, and protein restriction may be the best form of caloric restriction.

In detail...

• In pharmaceuticals, the prescription drug losartan (an angiotensin receptor blocker) is typically used to treat hypertension and high blood pressure. It may also have anti-aging benefits in combating sarcopenia and frailty by improving muscle remodeling and grip strength.

• In nutrition, recommendations were for walnuts, blueberries, and nectarines. Walnuts are good because they are the only nut containing a significant amount of alpha-linolenic acid (ALA), and because they are mainly composed of polyunsaturated fatty acids (PUFA, both omega-3 and omega-6) rather than monounsaturated fatty acids (MUFA), as most other nuts. Blueberries continue to be an important suggestion for anti-aging. They contain anthocyanins, antioxidants which may prevent inflammation and help to improve brain signals and memory function. The 2011 Blueberry Health Study reported that individual cognitive performance improved 1% over a one year period from consuming one half cup to two cups of blueberries per day. Necatrines (and acai) also have antioxidant properties and have been found to reduce oxidative damage and improve longevity in Drosophila melanogaster (Boyd, Free Radic Biol Med, 2011).

• A lifestyle anti-aging remedy was found in nonhuman primates. Heated hydrotherapy, e.g.; jacuzzis, two times a week for 30 minutes at 39-41 degrees C, induced heat shock response (which declines with age) and increased production of heat shock proteins 70 and 90 which resulted in reduced blood pressure.

• Exercise is always a good anti-aging improvement especially since 60% of U.S. adults over 60 have insufficient physical activity. Type II fibers (fast-twitch) are most vulnerable to aging so instead of trying to improve these, for older adults, it is better and easier to maintain Type I fibers associated with endurance exercise. For example, 70-80 year olds running 2-3 miles a few times a week had the glucoregulation profiles of sedentary adults in their 20s.
  

• Fasting, especially amino acid (e.g.; protein) deprivation, before chemotherapy and surgery was found to help in reducing injurious impact.

Conference report: interventional anti-aging

The focus of the 40th annual meeting of the American Aging Association held June 3-6, 2011 in Raleigh NC USA was emerging concepts in the mechanisms of aging.

Many usual topics in aging were covered such as dietary restriction (DR), inflammation, stress resistance, homeostasis and proteasome activity, sarcopenia, and neural degeneration.

Newer methods like microRNAs and genome sequencing were employed to investigate gene expression variance with aging and genetic signatures of longevity.

Aging as a field continues to mature including by using a systems approach to tracing conserved pathways across organisms, sharpening definitions of sarcopenia, frailty, and healthspan, and distinguishing interventions by age-tier (early-onset versus late-onset).

A pre-conference session on late-onset intervention concluded that there are numerous benefits to deriving such interventions.

Conference talks applied the biology of aging in a translational manner to intervention development.

• Using an individual’s own stem cells to regenerate organs for transplantation and as a cell source for cellular therapies could be a powerful near-term solution to disease.
  
• Several proposed interventions were pharmaceutical, myostatin inhibition, losartan, JAK pathway inhibitors, and enalapril for frailty and sarcopenia, and metformin to promote Nrf2 anti-inflammation response.
  
• In dietary restriction, protein restriction was found to be better than general calorie restriction. Short-term fasting may be helpful in chemotherapy, surgery, and acute stress, simultaneously increasing the killing of cancer cells by chemotherapy, while improving the survival of normal cells.
  
• Immune system interventions remain elusive, although statins may help to improve cellular-senescence promoted bacterial infection.
  
• Engineered enzymes may be useful in lysosomal catabolism.
  
• Dietary restriction mimetics, most promisingly involving TOR (TORC1 inhibition and rapamycin), may be more feasible than dietary restriction.

More details: Meeting Summary preprint.

VC life extension opportunity redux

The VC life extension investment opportunity could happen in at least three areas: first and most importantly, translational medicine, second, health social networks and third, distantly, standardized longevity treatments and delivery systems.

Translational medicine
The biggest and most obvious longevity play for VCs is in translational medicine, shepherding and commercializing science findings from basic research to patient therapies. The vast majority, perhaps even 90% or more, of basic research findings never go beyond the lab or journal publication. A particularly high profile example of an early stage longevity company that rocketed from test tube to IPO to big pharma acquisition is Sirtris, bought by GlaxoSmithKline for $720M in June 2008. Some other early stage translational medicine longevity startups are Elixir Pharmaceuticals, Juvenon and Sierra Sciences. In the plethora of remedies claiming science support, it is critical to tightly link the research evidence to the intervention. For example, in this year’s exploding brain fitness market, there is much claim of scientific support but little published clinical trial evidence.

Health social networks
Another VC play is health social networks (for example, PatientsLikeMe, CureTogether, DailyStrength, HealthChapter, Experience Project and peoplejam). Not only can patients connect and generate group-synthesized, curated and moderated knowledge, but health social networks can also facilitate the development of personalized medicine by being a repository for the quantitative data of genomics, ongoing biomarker measurements and electronic healthcare records. Big pharma can approach patient communities for field studies and clinical trials.

Longevity treatment delivery
Standardized longevity treatments and delivery programs via private clinics are not a traditional VC play, but some interesting 10x business models may be possible. In the several years before longevity treatments are more proven and automatically administered via traditional healthcare channels, these services can be provided by private clinics as they are now.

What would improve the longevity treatment market is standardization; standardization of doctor qualifications, certifications, validations, services and treatments, and treatments supported by scientific research clearly evidenced to consumers. Currently, longevity doctors offer heterogeneous suites of services which is challenging for consumers to parse. Positioned appropriately, there is more than adequate demand despite the current lack of insurance reimbursement. Since longevity treatments are currently outside the purview of traditional medicine, third party certification (for example led by the Methuselah Foundation) could help validate doctors and treatment programs, and contribute to industry standards.

Next big VC market: life extension?

Life extension is a growing market and could be the next significant industry targeted by Venture Capitalists and private investment as alternative energy and clean tech eventually wane. The opportunity is made obvious by continuous soaring costs in the world’s largest industry, healthcare, unfunded Medicare type liabilities in every industrialized country, and the demographic aging of populations and below replacement fertility rates together with massive demand and willingness to spend on longevity remedies.

What is the Life Extension Market?
The life extension market is the commercialization of scientific findings from stem cell, immunology, cancer, regenerative medicine and other areas of research. The research linkage between products and research will hopefully become stronger and more standardized. For example, many longevity remedies available today claim scientific support. This research could and should be linked to the products online (23andme is a nice example of research linkage) so consumers and other interested parties can research the products themselves. Bloggers and other independent intermediary watchdogs could synthesize the scientific research and confirm or deny the product claims.

Longevity Docs Needed
It is not clear that traditional physicians will be those prescribing longevity remedies. Specialist longevity docs are needed and will likely arise and market themselves as such, there are a few examples of this today. Most traditional physicians do not currently have expertise in new areas such as longevity and personalized genomics, or the enhancement and prevention vs. cure mindset.

Supplements, Hormones and Enzymes
The first step in life extension treatments is supplements, ranging from a daily multivitamin to the 200 or more supplements per day taken by futurist Ray Kurzweil. The next step is hormone and enzyme replacement therapies, which must generally be overseen by a physician. A variety of treatments have been undertaken per the shifting legal climate, not everyone wanting to be restored to the hormonal levels of their twenties and other reasons.

Longevity Social Network
It would be great to have a health social network (HSN), like PatientsLikeMe and CureTogether for the longevity community. First, people could share the different interventions they are trying. Second, they could upload their ongoing bio-marker test data into an aggregated electronic health record, similar to what Google Health is contemplating, to track and possibly share the impact of the interventions. Third, companies with research and therapies targeting this market could contact an aggregated group to propose field studies, clinical trials and offerings. For example, the 23andme Parkinson’s community has been contacted for such research.

Status of Research on Human Aging

Longevity is the new alternative energy
With $10m quickly raised by the Methuselah Foundation, VCs just beginning to see the opportunity and continually soaring healthcare costs, the longevity market could easily become as big as the alternative energy/climate change solutions market has become now.

Longevity research status
Grossly generalizing, the main focus in aging research is figuring out how to get processes that already occur, in the young and in cancer for example, to occur at other times, in the old. The optimum approach may include both reverse engineering and forward engineering in the form of synthetic biology as has been successful in other biological research areas like gene synthesis.

Aging is multidisciplinary, comprising at minimum the study of stem cells, immunology, cancer, DNA damage, tissue engineering, genetic engineering, regenerative medicine and micronutrients.

A comprehensive collection of anti-aging research findings was presented at the Aging 2008 conference June 27-29 at UCLA. The current developmental stage of aging research is early, perhaps in the second inning. Groundwork is being laid, phenomena are being documented, understanding of general mechanisms is sought, existing processes are being enumerated and early cycles of testing have begun primarily on flies and mice.

The seven primary causes of aging are DNA mutations in the cell nucleus and mitochondria, junk that builds up inside and outside cells, cells sticking together and cell loss and death. These are described at length, together with potential solutions, in aging research pioneer Aubrey de Grey’s book, Ending Aging and in the journal Rejuvenation Research. De Grey’s organization, the Methuselah Foundation, provides grants to anti-aging researchers. Some of the freshest thinking so far has included biomedical remediation, therapeutic organisms purpose-catalyzed in the body and the possibility of removing the overly-prone-to-damage mitochondrial DNA.

Generalized summary of Aging 2008 research findings:

• Applying (non-individual specific) substances from the young to the old appears to work
• With aging, not only does "good stuff" (cells, processes, etc.) decline but "bad stuff" also arises
• The quality of the biological environment facilitates or inhibits activity and repair
• Treatments may be most effective when begun in youth or middle age
• The goal is to extend healthspan not just lifespan

DIY biohacking and the cocktail problem
Every bit as interesting as the scientific talks were the informal discussions of the wide range of interventions, treatments, supplements and other anti-aging remedies in use by conference participants. The cocktail problem is how multiple remedies taken in concert may be impacting each other. Never has there been a market with such demand and so few offerings as for anti-aging remedies.