A Good Scientific Polemic on Aging
It is good that scientists are now more willing than in past years to talk about human longevity and the prospects for reversing aging through medical science. That change in attitudes is a necessary part of creating an environment in which rejuvenation research programs like SENS can thrive.
This particular group of researchers holds a different view as to which of the known changes in old cells and tissues are fundamental and thus cause aging: in the SENS outline telomere shortening is a secondary effect and nuclear DNA damage is only a cause of cancer rather than aging, but this paper puts them front and center as primary causes of aging. These researchers are also as yet unwilling to explicitly talk about rejuvenation rather than simply slowing aging, but a rising tide floats all boats.
All in all I'm very pleased to see scientists independently following the SENS model by producing a work that combines (a) specific descriptions of the changes proposed to cause aging and (b) specific proposals on how to use this information to build therapies that will address aging. The paper is open access for the moment at least, so you might take a look:
For some species, living twice as long in good health depends on no more than a few genes. When this fact was revealed by studies on worms three decades ago, it ushered in a golden age of ageing studies that has delivered numerous results, but also sown some confusion. [Researchers are now] publishing an exhaustive review of the subject that aims to set things straight and "serve as a framework for future studies." All the molecular indicators of ageing in mammals - the nine signatures that mark the advance of time - are set out in its pages. And the authors also indicate which can be acted upon in order to prolong life, while debunking a few myths like the belief that antioxidants can delay aging.The authors are Spanish scientists Maria Blasco (Spanish National Cancer Research Centre, CNIO), Carlos López-Otín (University of Oviedo), and Manuel Serrano (CNIO), along with Linda Partridge (Max Planck Institute for Biology of Ageing) and Guido Kroemer (Paris Descartes University). Their inspiration came from a classic 2000 paper, The Hallmarks of Cancer, [which] marked a watershed in cancer research.
[This] removes the "frivolity" with which aging research is often approached: "It's not about not having wrinkles or living to be a hundred at any cost, but about prolonging disease-free life." [The] scientists are explicit about their final goal, which is "to identify pharmaceutical targets to improve human health during aging."
Another milestone of the paper is that it not only defines the nine molecular hallmarks of aging but orders them into primary hallmarks - the triggers; those that make up the organism's response to these triggers; and the functional defects resulting. This hierarchy is important, because different effects can be achieved by acting on one or other of these processes. By acting on just one mechanism, if it numbers among the primaries, we can delay the aging of many organs and tissues.
There are four primary causes of aging: genomic instability; the shortening of telomeres; epigenetic alterations; and loss of proteostasis.
Genomic instability refers to the defects the genes accumulate over time, due to intrinsic or extrinsic causes. The shortening of telomeres - the protective caps over the ends of chromosomes - is one such defect, but so important a one that it stands as a hallmark in its own right. Epigenetic alterations are the result of lived experience - our exposure to the environment.
Loss of proteostasis has to do with the non-elimination of defective proteins, whose accumulation promotes age-related diseases. With Alzheimer's, for instance, neurons die because plaques form of a protein that should have been eliminated.
The organism responds to these triggers with mechanisms that try to correct the damage, but which can themselves turn deleterious if they become exacerbated or chronic. This is the case of cellular senescence: the cell is induced to stop dividing, and thus prevent cancer, when too many defects are built up, but if the effect is overdone, the tissues - and the body - age.
One therapeutic strategy tested successfully in mice is to stop the telomeres from shortening. "The process can be halted and even reversed in mice," remarks Blasco, an expert in the area, who is convinced that, by and large, "we still have ample room for manoeuver to combat aging and enjoy more years of both life and health."
For López-Otín, "We have diverse opportunities to extend longevity in the not too distant future. Treatments aimed at reducing or correcting the genomic damage that occurs with time are still a distant prospect, but those focusing on metabolic regulation systems may be much more achievable. We don't aspire to immortality, just to the possibility of making life a little better for us all."
Link: http://www.eurekalert.org/pub_releases/2013-06/cndi-srw060313.php
That was a good review overall, and their summary of causes is not as incompatible with SENS as it might appear. Genomic instability might be a root cause of ageing, but what are its immediate consequences? Usually it will result in cell loss (one of the 7 deadly things), cellular senescence (part of another of the 7) or cancer, which is also covered. The reason, I think, for not including genomic instability as a cause of aging for the purpose of the SENS technology program is that it is such a non-starter from the perspective of interventions, as these authors acknowledge. In that case, it is best to look for downstream causes (but still to intervene as early in the causal chain as reasonably possible). After all, we could look even further up the causal chain and find that genomic instability is caused by cosmic rays and brownian motion. Short of cryonics and deep mineshaft repositories, it's of course impossible to address those causes, so we look downstream until we find something that can be addressed, but not further.
I do have a problem with the term "loss of proteostasis." The problem is that it implies that there is a salubrious condition of "proteostasis" when all the proteins are properly disposed, but there is no evidence at all that this is the case. Rather, there is never "proteostasis" and the damaged proteins and other biomolecules progressively accumulate from the beginning. Framing the issue the way they do is deceptive.
I just wanted to express praise for Jose's comment. It's very unusual to see quite such an accurate understanding of SENS, its logic, and its relation to the ways that other experts describe damage accumulation. Jose, who are you exactly? - it's time you worked for me :-)