MMP inhibitor to kill senescent cells

Important work in the understanding and remedy of aging at the Buck Institute’s Systems Biology Symposium of Aging held November 10-13, 2009 was presented by Judith Campisi in a keynote talk, “The Four Horsemen – Damage, Inflammation, Cancer and Aging: Integrating Aging and Age-Related Research.”

Summary
Campisi has found a common biological explanation for the related phenomena of aging, degenerative disease and cancer: the senescence-associated secretory phenotype (SASP). Senescent cells produce the SASP, essentially inflammation, which can then trigger degenerative disease (aging) and hyper-prolific disease (cancer). A potential solution is to remove the 10-15% of senescent cells that are not naturally killed by the immune system by using matrix metalloproteinase (MMP) inhibitors.

Background
Humans are much longer-lived than other organisms such as flies because they have evolved cell-dividing mechanisms for tissue regeneration and repair. However, mistakes in the form of mitotic mutations occur during this process and build-up cumulatively which can cause cancer. To counter the build-up of mutations, tumor suppressor mechanisms evolved. One action of gate-keeper tumor suppression mechanisms is to direct damaged cells to senesce, or lose function.

Senescent cells are not harmless, they amass at sites of inflammation and pre-cancer and secrete up to 40 different cytokines (immunoregulatory proteins) which together can be thought of as the SASP secretome. All major age-related diseases share an inflammatory pathogenesis including atherosclerosis, myocardial infarction, stroke and metabolic syndrome. The build-up of senescent cells can lead to both degenerative disease (aging) and hyper-proliferative disease (cancer).

The purpose of the cytokines is to repair tissue. In the SASP secretome, they are perhaps trying to summon the immune system, communicating to the rest of the tissue that there is a problem. The immune system does arrive and kill most senescent cells, but 10-15% survive, perhaps due to the over-expression of matrix metalloproteinases (MMPs) which can cleave the ligands off the cell surface where natural killer cells would bind, allowing the cell to escape the immune system.

Solution
Extending the existing research and application of matrix metalloproteinase (MMP) inhibitors, chemicals that mimic the binding site, Campisi’s lab has been able to drive senescent cell killing to 95%.

Aging is solvable

That aging is understandable and solvable, not necessarily immediately but ultimately, was one topic not seeing a lot of opposition at the American Aging Association (AGE) conference in Phoenix AZ May 29 – June 1, 2009. Key research highlights are below.

Aging is a key contemporary concern, on the order of climate change, as all countries worldwide have populations increasingly stratified towards aging. Aging is not just a medical condition but a key challenge to be resolved for advanced societies to be successful in the long-term. Productivity, healthcare costs and happiness and comfort could all be improved with advances in the remedy of aging. Aging has advanced from a nebulous concept to concrete mechanisms that can be understood and managed. Thematically, most of the bioparts impacted in aging (cells, genes, proteins, neurons, etc.) seem to still be present in older organisms, just not functioning the way they did when the organisms were younger, suggesting that it may be possible to manage and reverse aging processes, and confirming the systemic nature of aging including, for example, the role of a healthy microenvironment and cell-cell signaling. Reductionism as an approach has proved unsuccessful.

Aging is a multidisciplinary phenomenon, involving different deterioration processes in different tissues over time. Aging involves a variety of fields (immunology, cancer, regenerative medicine, cognition, micronutrients, etc.) and a variety of levels of research species (C. elegans (worms), Drosophila (flies), mice, rats and humans). At AGE, the organizational structure was a focus on systems pathways, particularly signaling and hormones, together with a look at the role of proteins in aging.

AGE was an excellent place to obtain a broad and deep comprehension of how aging works. The systemic rigor required to characterize the process-intensive nature of aging has been making significant progress, with a much more detailed understanding of the complex nested multifactor pathways now existing as compared with that of even a few years ago. It is clear that the painstaking characterization work could be further improved with automation and quantitative tools, especially for example, digital linkage of aging pathways across organisms.

As with other life sciences areas, the potential widespread quick and cheap availability of the sequencing of genomes, proteomes, etc. is likely to dramatically change how the science of aging is conducted, though not guarantee quick solutions. As pathways continue to be confirmed, they can be digitized into software and nearly indefinite simulated iterations could be run before conducting time-consuming and expensive bench experiments in confirmation.

Many interventions work for extending the lifespans and healthspans of lower order organisms, for example knocking out any one of 200 known genes may extend the lifespan of the C. elegans worm but the specifics and replicability of the mechanisms in higher order organisms are not known. It does not make sense to directly translate point solutions up to mammals given the systemic nature of the organisms and aging processes. Even moving one biomarker for alcohol consumption from monkeys to humans is not direct.

Exciting new research findings
Reference links below and conference abstracts here

1. 3-D organ printing: Use only biologics (cells and cell products) in a scaffold-free tissue engineering process to print 3-D tissues and organs which can be vascularized prior to implantation, relying on developmental biology to trigger the cells to fuse and self-assemble into organs. (Gabor Forgacs, video, lab, organ printing)
   
2. Stem cell antibodies: Improve existing cardiac stem cell therapies (only 1% of cells reach the intended destination) by using specific antibodies for better targeting and retention of stem cells at sites of tissue injury. Replace cardiomyocytes with adult stem cells. (Jim Larrick, paper, general information)
   
3. Stem cells: Amplify and rejuvenate adult stem cells for injection into knees and hips as an alternative to surgical replacements. (Regenexx)
   
4. Bioremediation: Use natural enzymes to remediate biological build-ups; cholesterol oxidase from Brevibacteria to reduce 7KC cholesterol in atherosclerosis and A2E-degrading enzymes to improve macular degeneration. (John Schloendorn, research program, paper)
   
5. Life extension: Examine the mechanisms of dietary restriction (DR) with further elucidation of TOR (target of rapamycin) pathways, a fast growing area of research. Find that inhibiting a downstream gene in the TOR pathway, HIF-1 (a transcription factor important for growth and metabolism), extends lifespan in worms. (Pankaj Kapahi, paper)
   
6. Life extension: Generate a 10x lifespan extension in C. elegans by silencing many components of insulin/IGF-1 signaling (IIS) possibly via the disruption of PIP3 (a key signaling molecule required for the membrane tethering of many signaling molecules). (Puneet Bharill, paper)
   
7. Amyloid plaque reduction: Use a known plaque imaging agent, ThT (Thioflavin T), as a therapeutic for amyloid plaques. (Silvestre Alavez, lab affiliation, paper)
   
8. Cancer protection: Find that naked mole rats have two layers of anti-cancer protection, humans have only one. p16 is the first-line-of-defense anti-cancer protection mechanism found in naked mole rats. Humans (and other organisms) also have p16 (a suite of three genes), perhaps the mechanism for its upregulation (probably a cell:cell signaling dynamic) in naked mole rats could be understood and turned on with an enzyme in humans. (Andrei Seluanov, earlier research)
   
9. Cognitive function: Find that neurogenesis is possible in aged organisms with exercise followed by cognitive stimulation (e.g.; tackling a puzzle or challenge); organisms can benefit by building up a larger reservoir of brain cells earlier in life by being exposed to a variety of external stimulation. (Gerd Kempermann) This author’s speculation: Perhaps neurogenesis could be further harnessed for brain enhancement beyond currently realizable human capacities as this mechanism is better understood.
   
10. Aging biomarkers: Upstream the aging focus to prevention by measuring biomarkers and introducing interventions. Some suggested biomarkers of aging are p16 gene levels (which can be decreased with exercise), telomere length, the level of senescent cells, and the number of circulating lymphocytes in the immune system (measure total T cells (CD3+), B cells (CD19+) and CD28 absolute numbers on CD8+ T cells). (Kronos research projects, test menu; telomere length measuring)
    
11. Hormones-IGF: Find no conclusive evidence of insulin-like growth factor's (IGF) ability to retard natural aging, though on an individual basis some people may find it useful. (Marc Blackman)
    
12. Hormones-HRT: Find that hormone replacement therapy (HRT) can be good for improving cognitive function and bone loss in women that do not have a risk of heart disease; HRT should be started with the onset of menopause, not later. (Barbara Sherwin, Eef Hogervorst)
    
13. Cost of reproduction: Find that ovary removal in grasshoppers resulted in a 25% increased lifespan, contributing to existing evidence regarding the high cost of reproduction. (John Hatle) This author’s speculation: In the farther future, in humans, it could be quite desirable to closely manage fertility, turning it on and off at will, if fertility is even necessary.
    
14. Micronutrients: Find tremendous nutritional benefits from the consumption of fruits with skin, especially blueberries (pterostilbene that reduces oxidative stress), blackberries, raspberries, red grapes, pomegranates, cranberries, plums, strawberries, cherries, pears and apples (phytochemicals that provide cancer prevention), walnuts (preventing the inflammation and oxidative stress of brain aging:), green tea (catechins that reduce cardivascular and cancer risk) and tempeh (fermented whole soy bean with folate is healthier than tofu (processed soy bean curd)). (Blueberries: Agnes Rimando, Rolf Martin; Apples: Rui Hai Liu, Walnuts: James A. Joseph, Green tea: Vojo Deretic, Tempeh: Eef Hogervorst)
    
15. Calorie restriction (CR)/dietary restriction (DR): Find that in humans, improved biomarkers for CR/DR, vegan and raw food diets that result in the extension of the onset of aging challenges. (John Holloszy)
    
16. Aging mice testbed: A mouse type that sufficiently recapitulates early aging, the human WS phenotype (Werner syndrome), has been created which could hasten mammalian aging research. (David Kipling)
    

Conclusion
Aging is a key contemporary issue. Research is advancing both incrementally and radically in every area of aging. The highest immediate impact could come from working on aging problems upstream at important fulcrum points that impact everything below them, such as genetics, epigenetics and the immune function. The research is progressing and it is starting to be time for VCs, big pharma and DIYbio’ers to take advantage of the many interesting and actionable possibilities.

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.