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The Seven Pillars of Aging

Aging research is still mostly a matter of investigation, gathering data and validating theories without a hint of any intent to build treatments to help the aged. This terrible state of affairs is changing, however, and the prospects look increasingly good for serious levels of funding to arrive over the next decade at established research programs aimed at intervening in the aging process. Hence a lot of researchers are now interested in establishing such programs, and the existing programs are solidifying their positions and networks. It is often thought that scientists have a poor instinct for finance and competition, but the people who think that have evidently never seen the long game of grant management in action. A great deal of planning, positioning, and forethought takes place among those who manage sizable research portfolios.

Most of today's longevity science programs with an aspiration to producing therapies are presently focused on very modestly slowing aging through metabolic manipulation of one kind or another, such as the development of calorie restriction mimetic drugs. This is unfortunate, but I suppose that there has to be a start somewhere. When those programs are raising funds at five or ten times their present level, despite the poor prospects for any sort of meaningful extension of healthy life to emerge from their work, the same multiplier in funding levels will be attainable for SENS rejuvenation research. SENS-style biotechnologies that can repair the underlying cellular and molecular damage that causes aging are the approaches that actually matter if what you care about is adding decades of healthy life and restoring the old to vigor and health. SENS is still the young, disruptive movement in the field, but a rising tide floats all boats.

That said, SENS has rather set the tone for how researchers are choosing to present their research strategies: plans of development leading towards specific therapies to treat the aging process itself. This is a departure from the present state of medicine, in which only the symptoms of aging are treated, the various age-related diseases. Pushing the research community towards a growing consensus that aging can and should be treated as a condition (or rather collection of identifiable conditions) is a great victory in and of itself: now it's just a matter of steering in the right direction, funding the best strategies. SENS is presented as a set of seven classes of damage that causes aging, each with its own attendant proposed paths to treatments. The influence of that vision can be seen in the noted Hallmarks of Aging polemic published last year, which followed the same model but with a different, overlapping emphasis on what in aging is thought to be cause versus consequence.

Now here again we have another new position statement on treating aging that echoes the SENS model. It is put forward by leading figures in the research community, with yet another another take on what is cause versus consequence, and which research strategies to pursue, also overlapping to some degree with the SENS vision - though less so, I think. It is no doubt completely coincidental that there are seven pillars of aging, perhaps a reference to Proverbs 9:1, and it is certainly the case that all of these strategic considerations of aging research could be differently divided if the fancy takes you. But seven is a magic number it seems, and so seven it is:

Leading scientists identify research strategy for highly intertwined "pillars of aging" as next step in supporting the trans-NIH Geroscience Interest Group's efforts to integrate aging into research on chronic diseases

Scientists who have been successful in delaying mammalian aging with genetic, dietary and pharmacological approaches have developed a research strategy to expand Geroscience research directed at extending human healthspan. The scientists took part in the first summit of the NIH Geroscience Interest Group (GSIG) held last year on the NIH campus. The National Institutes of Health is made up of 27 different components called Institutes and Centers. Each has its own specific research agenda. The GSIG is aimed at promoting new pathways for collaboration, both within the NIH and with its funded researchers, specifically within the context of aging.

The "Pillars of Aging" and research goals are detailed in the following table:

Adaptation to Stress

  • Bridge continuum from psychological to molecular stresses.
  • Differentiate hormesis from toxic stress.
  • Better align human and animal studies.

Epigenetics

  • Biomarker development: chronological vs. biological aging.
  • Link age-related environmental inputs to epigenetic signatures.
  • Test small molecules that regulate enzymes controlling epigenetic events.

Inflammation

Macromolecular Damage

Metabolism

  • Define role of signal transduction pathways linked to metabolism in aging processes.
  • Understand contribution of circadian clocks to aging and metabolism.
  • Connect metabolic dysfunction with tissue-specific decline in aging.

Proteostasis

  • Identify proteostatic pathways that are overwhelmed in specific chronic disease states.
  • Examine crosstalk between proteostasis machineries.
  • Understand non-cell-autonomous signaling and activation of proteostasis pathways.

Stem Cells and Regeneration

"We have high hopes that our research strategy will help move collaborative efforts to the next level. What has come out of our work is a keen understanding that the factors driving aging are highly intertwined and that in order to extend healthspan we need an integrated approach to health and disease with the understanding that biological systems change with age. The trans-NIH GeroScience Interest Group (GSIG) and this Geroscience initiative hope to mobilize the research community about considering prevention of multiple age-related chronic conditions by targeting common mechanisms underlying these conditions, rather than improving the management of diseases one by one. Our current approach to researching and treating chronic diseases is inadequate and fragmentary. By the time chronic diseases are diagnosed, much damage is done and undoing it is difficult. Targeting aging may allow early intervention and allow us to maintain vigor and activity, while offsetting the economic burdens of a burgeoning aging population hampered by multiple chronic diseases."

I see much of this, such as the focus on epigenetics, metabolism, stress, and proteostasis, as being largely a case of looking at the consequences of damage and the detailed operation of damaged machine. It is vastly complex, and not a path to prevention or reversal of aging. Nonetheless, that is where the overwhelming majority of today's research takes place. Still, most of the research community does see aging as being the result of damage, even though you might not be able to discern as much from their research work, and so there are components of these pillars that are pointed in the right general direction.

Comments

I think the Buck institute would have better luck attempting to market their labcures site or just sticking to senescent cells. There's no tractability in anything in that list from what I can see... except for redundant information on stem cells.

Posted by: Michael-2 at November 11th, 2014 1:45 AM

The Buck Institute's labcures site doesn't seem to be raising much revenue so far unfortunately.

There was a great article on medium about letting millionaires pay $2 million dollars to be part of a physician lead investigation for themselves with a new untested cancer treatment while paying for 20 people to get the treatment in a stage 1 trial.

But even if that funding model takes off, would it work in aging research where treatments are still in the basic science phase? And where the millionaire doesn't have the threat of imminent death?

Posted by: Jim at November 11th, 2014 6:15 AM

@Michael-2: The Buck Institute publicity page is just the easiest link, as the actual paper isn't open access. It's more of a broad position statement by a group that happens to include some of the Buck Institute researchers.

http://dx.doi.org/10.1016/j.cell.2014.10.039

Posted by: Reason at November 11th, 2014 6:19 AM

I was going to say it does sound like a broad position statement that attempts to satisfy every researcher involved. It seems akin to political statement where the outcome and the goals are not so clear but includes a lot of rhetoric that no one could really disagree with.

For example do we really need ad nauseum studies on obesity? Obesity is bad for you in a lot of ways, don't get obese.

On the whole this is why SENS appeals to me because it outlines very easily the causes of various diseases and the mechanistic intervention that would yield some medium term results.

Posted by: Michael-2 at November 11th, 2014 6:34 PM

It's interesting to see the emergence of multiple strategies for organizing longevity/aging research. I'd like to see a three-way, side-by-side comparison of the SENS strategy, this "Seven Pillars of Aging" strategy, and the "Hallmarks of Aging" from Cell (http://www.cell.com/abstract/S0092-8674(13)00645-4) Just how mutually supportive are they? To an interested lay person like myself, they seem to confuse the situation.

Here is an example. The Hallmarks of Aging strategy prioritizes four of its nine categories as "Primary", three as "Antagonistic", and two as "Integrative." (http://www.cell.com/action/showImagesData?pii=S0092-8674%2813%2900645-4) This seems to help prioritize where the near-term research bets should be placed, while the Seven Pillars of Aging table, seems to just put all 20 of its "important goals" on equal footing, providing little prioritization guidance. I believe SENS also puts its Seven areas on equal footing. It seems that there are probably some areas that should be prioritized, the ones that cause the earliest and/or most irreparable signs of aging. The ones that pose as the "shortest fuse" to aging.

Posted by: Don Leatham at November 20th, 2014 1:05 AM

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