A Focus on Regulatory Systems in Aging

Much of modern aging research, too much in my view, focuses on regulation of aging and the prospects for changing regulatory processes to modestly slow the progression of age-related frailty and disease. Aging is caused by the accumulation of a few types of cellular and molecular damage and so these regulatory processes and their changes in aging are largely reactions to that damage. They are the wrong place to be intervening for best effect, and the focus should instead be on repair of the root cause damage. That remains a minority view at this time, unfortunately, which is why it is so important to raise enough funding to produce definitive proof of its greater effectiveness as a basis for therapies.

This paper is more indicative of how a majority of researchers think about the situation, however. This view explains why those interested in enhancing longevity are most often found working on expensive, marginal ways to alter the very complex reaction to damage rather than addressing the damage itself:

In the consideration of life-extending effects of aging-modulating drugs, a logical error can occur as a result of reductionist thinking peculiar to gerontologists in the middle of the last century when major aging theories including the free radical theory of aging were proposed. From the reductionist point of view, the organism was considered as a sum of relatively independent processes and mechanical components, and interventions designed to prolong life were seen as those being similar to car repairing. If this were indeed the case, then it would be possible to slow the rate of aging by affecting molecular pathways that influence specific aspects of aging, analogous to how antioxidants can slow down the rate of aging of plastic.

However, by summarizing the accumulated information, one can conclude that a reductionist approach in experimental gerontology has proved rather ineffective until now. This is not surprising, since aging is a classic "complex trait," in other words, a trait that is influenced by a plurality of genetic pathways. For example genome-wide research in Drosophila shows that hundreds of genes are involved in the control of aging. Therefore, it seems very difficult, if not impossible, to develop effective pharmaceutical interventions that may slow aging and extend longevity by targeting single genetic pathways.

On the contrary, more modern systemic ("holistic") thinking considers the organism as a whole. Taking into account the complexity of the aging process, the systemic approach addressed primarily to central regulation mechanisms seems more appropriate to developing aging-modulating treatments. From a systemic point of view, aging is not a disease in the sense of being caused by disturbance in several specific pathway(s), but is rather an inevitable consequence of realization of some (probably still substantially unknown) central regulatory processes making the organism more vulnerable to disease with age. According to these conceptual frameworks, the aging process is not primarily a result of accumulation of stochastic damage but is rather a co-product of developmentally regulated processes.

One potential mechanism of central regulation of the whole life cycle including aging is a process of epigenetic control of gene expression having important features in the given context. Indeed, it is: (1) potentially adaptive; (2) linking development and aging; (3) generalizing at the whole-organism level.

Link: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4271728/


This is a question for Michael Rae, when he gets a chance to answer:

does SENS has a rough estimate how much money are needed for the main programs (RepleniSENS, OncoSENS, MitoSENS, ApoptoSENS, GlycoSENS, AmyloSENS, LysoSENS) to make the breakthrough and bring these programs into real world?

That would be good to know to plan for further fundraising efforts.
The things I see them right now, is that while this community raised $150 k last year, that is very, very little. Funds needs to be somewhere at (at least) a 100X that sum to start seeing some results.

If we have a rough cost associated with these programs, we can work it back and come up with creative ideas to improve the donation process, to help as much as possible.


Posted by: Adrian Crisan at January 19th, 2015 12:15 PM

@Adrian: Last time I hear about that, it was $100M yearly during 10 years to double the life expectancy of a middle-aged mouse.

Posted by: Adrian at January 19th, 2015 12:26 PM

I severely doubt that a majority of (serious) researchers agree with any of this paper. This paper isn't research; it's just basically an anti-science screed written by someone who doesn't understand the fundamentals of engineering and cheerfully misinterprets several other papers.

For example, take this cited paper. There, the researchers make a case that some aspects of aging are the result of developmental processes run amok beyond what they were originally for. This guy attempts to mentally transform that into "central regulatory processes" (there are no truly central regulatory processes; if there were, we'd already have functional anti-aging treatments).

Also, some ridiculousness: "interventions designed to prolong life were seen as those being similar to car repairing. If this were indeed the case, then it would be possible to slow the rate of aging by affecting molecular pathways that influence specific aspects of aging, analogous to how antioxidants can slow down the rate of aging of plastic." What? Pure non sequitur - doesn't this guy know anything about how cars are repaired? You don't slow the gradual wearing down, you fix what's broke, piece by piece! And his use of verb tenses is just pure antagonism.

There's no meat to any of this, nothing useful. It's just basically "Stop trying to take aging apart! It's really really complicated so you can't do that! Believe in these made-up 'central regulatory processes' instead!"

Posted by: Slicer at January 19th, 2015 12:33 PM

@Adrian Crisan: See here:


The expectation is that SENS is priming the pump and much of the funding will flow from other organizations when things start to move. Look at movement towards senescent cell ablation, where much of the more recent research isn't actually funded by the SENS Research Foundation - expect that to happen as soon as broader support starts to emerge for any given field, once the most basic research is out of the way and things are looking promising.

Posted by: Reason at January 19th, 2015 2:06 PM

I wouldn't go so far as to call the paper "anti-scientific" or "screed" but its reasoning is more than a little deficient. The author starts off with a cogent if not particularly illuminating recitation of some of the problems with past projects to discover and develop gerontologically-motivated anti-aging pharmaceuticals. It's in going from this to a repudiation of stochastic damage accumulation as the cause of aging that there's a big logical leap.

In support the paper seemingly offers only that while damage-based theories of aging have predominated there have been no effective anti-aging therapies created. That argument's force is diminished by the author himself as he just earlier pointed out various flaws in the past approaches to developing treatments — flaws having nothing to do with an underlying damage-based paradigm. Thus the potential of the damage-based paradigm was in no way exhausted by flawed efforts in the past. Setting up the "holistic" perspective as a "modern" alternative is just some chronological snobbery.

Posted by: José at January 19th, 2015 5:12 PM
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