The focus of the 40th annual meeting of the American Aging Association, held a few weeks ago in North Carolina, was emerging concepts in the mechanisms of aging.
Most of the usual topics in aging were covered, such as dietary restriction, 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.
Many of the conference talks had a translational focus, applying the biology of aging to the development of anti-aging interventions:
- 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 caloric 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.
- Dietary restriction mimetics, most promisingly involving TOR (TORC1 inhibition and rapamycin), may be more feasible than dietary restriction.
- Immune system interventions remain elusive, although statins may help to improve cellular-senescence promoted bacterial infection.
- Engineered enzymes may be useful in lysosomal catabolism.
Major conference sessions, summarized below, highlighted microRNAs and the epigenetics of aging, the comparative biology of aging, stress resistance in aging and disease, translational aging research, the environment and aging, cardiovascular aging, and late onset interventions against aging.
Late-onset intervention against aging: tools, approaches, impact
A pre-conference meeting investigated late-onset intervention against aging, finding that appropriate interventions may vary by age group. Even if late-onset interventions are challenging, time-consuming, and expensive to develop, they are still desirable given the substantial economic, political, and personal benefits. A quantitative analysis considered a variety of life extension scenarios, and determined that overpopulation or other concerns would be unlikely to arise even in aggressive cases.
MicroRNAs: emerging tool for aging process elucidation and intervention
MicroRNAs (miRNAs, an abundant class of approximately 22-nucleotide small regulatory RNAs) were discussed as an emerging tool for investigating aging-related gene expression and the dynamic systems processes of aging. Over 900 miRNA genes have been identified in the human genome. Expression may vary dramatically over lifetime in different conditions of aging. MiRNAs may also be used as a leading indicator of aging, predicting the onset of aging-related disease as their levels change before aging is apparent in other ways. For example, p16 (a tumor suppressor) miRNA increases 1.2-fold per decade, an average of a 16-fold increase over an eight decade human lifespan. A second example is that miR-71 expression patterns in early adulthood have been found to correlate with lifespan in worms. It may be useful to target miRNAs in anti-aging interventions, for example through selective deletion. Adding to the complexity, MiRNAs are themselves subject to a variety of complex posttranscriptional regulation processes.
Comparative biology: naked mole rats, endocrine aging, telomere length, and oxidative stress resistance
The comparative biology of aging was a lens for the discussion of aging process characterization in the naked mole rat (NMR), reproductive aging and the benefits of dietary restriction (DR) in the Rhesus Macaque, how replicative aging and repressed telomerase may have evolved, and Nrf2 dysfunction as a causal factor in age-related oxidative stress.
Stress resistance: fasting, amino acid deprivation, TORC1 inhibition and rapamycin, and Nrf2 activation
A number of stress resistance topics were discussed including the benefits of fasting in chemotherapy and acute stress, that amino acid (e.g., protein) restriction may be more important than caloric restriction, how the mechanisms of TORC1 inhibition and rapamycin in the TOR (target of rapamycin) pathway act to extend lifespan, and Nrf2 anti-inflammation activation through metformin.
Translational aging research: remedy of frailty and sarcopenia
A translational aging research session focused on ameliorating frailty and sarcopenia. Sarcopenia is characterized mainly as an excessive reduction in skeletal muscle mass, but also includes changes in adiposity. It is an ‘undefined’ condition in that it is not yet prescribable and does not have agreed-upon measurement parameters and cut-off points for intervention. One definitional approach could be measuring loss of function in physical performance, for example gait speed has been linked with survival in humans  as well as falls and Timed Up and Go (TUG) capability. Frailty, on the other hand, is a diagnosable geriatric syndrome which is defined by one or more factors: a decline in strength and activity, an increase in inflammation, involuntary weight loss, exhaustion, slow walking speed, and reduced grip strength. Proposed interventions were pharmacological including myostatin inhibition, losartan, JAK pathway inhibitors, and enalapril.
Personalized therapies: organ regeneration and stem cells
One of the most exciting, and possibly near-term solutions for aging-related conditions is regenerative medicine, using an individual’s own stem cells to recreate organs for transplantation and as a cell source for cellular therapies. Regenerative medicine efforts are currently underway in 20-30 organs, particularly at the Atala lab. There are also numerous uses for stem cell therapies, two for example are improving neural stem cell genesis and treating neurodegenerative disease, and ameliorating telomere dysfunction present in both aging pathologies and disease states.
Genetics and aging
In genetics and aging, research was presented suggesting that centenarians, while having the same disease mutational profile as non-centenarians, have other aspects to their genetic profile that indicate a signature for exceptional longevity. Other work found 27 specific longevity SNPs (single nucleotide polymorphisms), and demonstrated a means of measuring the rate of epigenetic mutations in aging.
Dietary restriction (DR) and DR mimetics
Dietary restriction (DR) is a known technique for increasing longevity in model organisms. As it may be infeasible to implement in humans, DR mimetics that would produce the same prolongevity impact are sought. This would likely be in the form of pharmaceuticals that would target the same pathways and proteins (e.g.; TOR, sirtuins, and AMP kinases) involved in the biophysical response to DR. TOR is a strong candidate based its conserved pathway across organisms and successful experimental results in animals.
Immune system and infection
The decline of the immune system is a central problem in aging. Research was presented discussing immune system impairment being exacerbated by viral infection and how cellular senescence may promote bacterial infection in addition to aging.
One nice aspect of aging conferences is that there usually are a few gems of information that can be applied immediately in humans, in this case in the areas of pharmaceuticals, nutrition, lifestyle, exercise, and fasting:
- In pharmaceuticals, Losartan is a prescription drug (an angiotensin receptor blocker) 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.
- A lifestyle anti-aging remedy was found in nonhuman primates. Heated hydrotherapy (two times a week for 30 minutes at 39-41 degrees Fahrenheit) 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, it is better and easier to maintain Type I fibers associated with endurance. 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 helps to reduce injurious impact.
A more detailed preprint of the official Meeting Summary is available here.
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