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.

Anti-aging research developments in rapamycin, sirtuins, and stem cells

The Third Bay Area Aging meeting was held at Berkeley on May 8, 2010.

One highlight was the emperor’s new clothes statement “Maybe C. Elegans (e.g.; worm) is not the correct model organism for human aging!”

A variety of research was presented, with four themes amongst the most interesting:

1. Role of rapamycin in preventing inflammation
Rapamycin (more technically known as the mammalian target of rapamycin (mTOR)), has long been examined in aging since it is a protein that regulates a range of cellular behavior including growth, proliferation, motility, and survival. Initially hoped to be useful in treating cancer, rapamycin later turned out not to kill tumors due to systems biology; when mTOR is given and the TOR pathway is knocked out, the ERK pathway is upregulated instead.

However new research presented by Remi-Martin Laberge (Buck) shows that there is hope for rapamycin in the context of inflammation prevention. The normal process is that DNA damage response leads to NF-kB (a protein controlling DNA transcription) activation which leads to IL-6/8 (inflammation-related proteins) buildup, but with an mTOR introduction of rapamycin, instead IL-1a (an immune-response regulator) is obtained which prevents inflammation.

The prevention of inflammation is thought to be critical in anti-aging as many aging pathologies start with inflammation which later escalates to waste-build up and tissue break-down. This work is part of ongoing SASP (senescence-associated secretory phenotype) research by the Campisi lab (recent papers on p53 and p38MAPK).

2. Role of recently discovered SIRT7 in oncogenesis
Matt Barber (Stanford) presented work regarding a recently discovered SIRT (Silent Information Regulator) protein. SIRT7 is a chromatin-associated protein and site-specific histone H3 K18 deacetylase. There is a potential connection with SIRT7 and oncogenesis in that SIRT7 interacts with ELK4 (a pathway upregulated in cancer) to suppress a tumor suppressive gene expression network and helps stabilize aggressive cancer phenotypes.

3. Enhanced stem cell therapies
Randy Ashton (Berkeley) showed research regarding the increased ability to dopaminergiacally pattern hESCs to facilitate regenerative therapies for Parkinson’s disease. This was accomplished by making a protein important in neural development, sonic hedgehog, more sensitive through polyvalency.

4. Protein homeostasis and proteasome activity necessary for long lifespan
Brett Robison (Buck) presented work suggesting that normal proteasome function is required for full lifespan in yeast. The proteasome is an important location for waste degradation in cells. Aging cells showed impaired protein homeostasis and decreased proteasome function but it is unclear if this is cause or effect. Theodore Peters (Buck) also showed that maintaining protein homeostasis is important for healthy aging.

VC guide to anti-aging biotechnology investing

Several promising startup companies focused on the nascent but obviously significant and growing anti-aging biotechnology space were present or discussed with interest at the recent SENS4 (Strategies for Engineered Negligible Senescence) conference in Cambridge, U.K., September 3rd – 7th, 2009 (program) (full conference report).

1. Epeius Biotechnologies, San Marino, CA, USA: Rexin-G, a tumor-targeted injectable gene delivery system
2. FoldRx, Cambridge, MA, USA: small molecule therapeutics to treat protein misfolding diseases, and bind and clear undesired molecules
3. Gencia Corporation, Charlottesville, VA, USA: mitochondrial DNA rejuvenation using the rhTFAM (recombinant-human mitochondrial transcription factor A) protein
4. Genscient, Fountain Valley, CA, USA: novel chronic disease therapeutics by combining genomics and selective screening (a large Alzheimer’s Disease genetic study is in progress with Kronos and TGen)
5. Knome, Cambridge, MA, USA: whole human genome sequencing (consumer offering)
6. Neotropix, Malvern, PA, USA: oncolytic viruses for the treatment of solid tumors
7. Pentraxin Therapeutics Ltd, London, UK: small molecule drug CPHPC specifically targeting SAP (serum form of amyloid P) and removing it from the blood and brains of patients with Alzheimer’s Disease
8. Repeat Diagnostics, Vancouver, BC, Canada: telomere length measurement for total lymphocyte and granulocyte populations (consumer offering)
9. Retrotope, Los Altos Hills, CA, USA: using isotope effect to slow down damage pathways and control metabolic processes associated with oxidative stress
10. StemCor Systems, Inc., Menlo Park, CA, USA: bone marrow harvesting system
11. T.A. Sciences, New York, NY, USA: telomerase activation via the single molecule TA-65, licensed from Geron Corporation (consumer offering)
12. TriStem Corporation, London, UK: retrodifferentiation technology to create stem cells from mature adult cells

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.