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Hallmarks of Aging (paper)


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#1 reason

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Posted 06 September 2013 - 09:36 PM


The open access Hallmarks of Aging paper was published earlier this year. It is an outline by a group of noted researchers that divides up degenerative aging into what they believe are its fundamental causes, with extensive references to support their conclusions, and proposes research strategies aimed at building the means to address each of these causes. This is exactly what we want to see more of in the aging research community: deliberate, useful plans that follow the Strategies for Engineered Negligible Senescence (SENS) model of approaching aging.
Read through the Hallmarks of Aging and you'll see that it is essentially a more mild-mannered and conservative restatement of the SENS approach to aging - written after more than ten years of advocacy and publication and persuasion within the scientific community by SENS supporters. To my eyes, the appearance of such things shows that SENS is winning the battle of ideas within the scientific community, and it is only a matter of time before it and similar repair-based efforts aimed at human rejuvenation dominate the field. Rightly so, too, and it can't happen soon enough for my liking. SENS and SENS-like research is the only way we're likely to see meaningful life extension technologies emerge before those of us in middle age now die, so the more of it taking place the better.
Aubrey de Grey, author of the original SENS proposals and now Chief Science Officer of the SENS Research Foundation that funds and guides rejuvenation research programs, is justifiably pleased by the existence of the Hallmarks of Aging. See this editorial in the latest Rejuvenation Research, for example:
A Divide-and-Conquer Assault on Aging: Mainstream at Last

On June 6th, a review appeared concerning the state of aging research and the promising ways forward for the field. So far, so good. But this was not any old review. Here's why: (a) it appeared in Cell, one of the most influential journals in biology; (b) it is huge by Cell's standards - 24 pages, with well over 300 references; © all its five authors are exceptionally powerful opinion-formers - senior, hugely accomplished and respected scientists; (d) above all, it presents a dissection of aging into distinct (though inter-connected) processes and recommends a correspondingly multi-pronged ("divide and conquer") approach to intervention.
It will not escape those familiar with SENS that this last feature is not precisely original, and it may arouse some consternation that no reference is made in the paper to that prior work. But do I care? Well, maybe a little - but really, hardly at all. SENS is not about me, nor even about SENS as currently formulated (though a depressing number of commentators in the field persist in presuming that it is). Rather, it is about challenging a profound, entrenched, and insidious dogma that has consumed biogerontology for the past 20 years, and which this new review finally - finally! - challenges (albeit somewhat diplomatically) with far more authority than I could ever muster.
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Aging has been shown, over several decades, to consist of a multiplicity of loosely linked processes, implying that robust postponement of age-related ill-health requires a divide-and-conquer approach consisting of a panel of interventions. Because such an approach is really difficult to implement, gerontologists initially adopted a position of such extreme pessimism that all talk of intervention became unfashionable. The discovery of genetic and wrong, slow, expensive, low-yield path for a couple of decades: the path of deciphering the mechanisms of calorie restriction and altering genes and metabolism to slightly slow down aging. This path cannot result in large gains in life expectancy and long-term health, and it cannot result in therapies that will greatly help people who are already old. What use is slowing down the accumulation of the damage of aging if you are already just a little more damage removed from death, and frail and suffering because of it, and the treatment will meaningfully alter none of that? If we want to add decades or more to our healthy life spans before we die, then rejuvenation and repair of damage are what is needed: ways to reverse frailty, remove suffering, and restore youthful function.

View the full article at FightAging

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#2 Darryl

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Posted 07 September 2013 - 01:31 AM

Nice review. It of course nicks its title, organization and even graphics from the hugely influential Hallmarks of Cancer paper from 2000.
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#3 CatFoodMoney

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Posted 07 September 2013 - 08:01 PM

Thanks for posting that link, Darryl.

#4 reason

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Posted 16 August 2016 - 12:11 PM

This open access review of the mechanisms of aging is a followup of sorts to the noted Hallmarks of Aging paper, in which researchers followed the SENS model of breaking down aging into a set of actionable causes. There is some overlap between the SENS view of molecular damage and the Hallmarks view of metabolic dysregulation - cellular senescence is noted in both, for example - but from a SENS perspective the Hallmarks list includes a lot of things that are either markers of damage or later consequences of damage, not causes of aging. This well illustrates what has long been a major challenge in aging research, which is that cellular biochemistry is so very complex that there is still plenty of room to argue over whether important mechanisms in aging and age-related disease are causes or consequences of one another.

Getting the relationships right is vital to the development of life-extending therapies, as only the treatment of causes will prove to be very effective - and as things stand most of the field is working on patching over consequences instead, a strategy doomed to be both expensive and produce only marginal benefits. The only way to settle these debates over cause and consequence any time soon is to produce rejuvenation therapies that actually work, which is one of many reasons why advocacy for SENS research and development is so important. Sadly, in this paper as elsewhere, the ambitions with regard to aging and longevity are small: giving a greater priority to adjusting diet and lifestyle is the primary conclusion found at the end, and we all know just how little that can achieve in the grand scheme of things. No lifestyle will give you more than very tiny odds of reaching a century of aging, and no lifestyle choice can prevent you from aging and declining along the way. Only biotechnology that addresses the causes of aging can do more.

The human superorganism (i.e., the host and its microbiome) is a complex metabolic system in which nutrient intake, physical activity, and elimination of waste orchestrate anabolic and catabolic reactions that ultimately determine development, maturation, and aging. After many years of being subordinate to the surge in cellular and molecular biology, the study of metabolism is now experiencing its own Renaissance. A clear understanding is emerging of the key roles that metabolites play in all biological processes, including physiological and pathological aging.

We have previously classified the nine candidate hallmarks of aging into three categories. The primary hallmarks (genomic instability, telomere attrition, epigenetic alterations, and loss of proteostasis) are the main causes of molecular damage underlying aging. The antagonistic hallmarks (deregulated nutrient sensing, mitochondrial dysfunction, and cellular senescence) mediate beneficial effects at low levels and protect the organism from damage and nutrient scarcity but become deleterious at high levels. Finally, the integrative hallmarks (stem cell exhaustion and altered intercellular communication) are the culprits of aging and arise when the accumulating damage cannot be compensated by homeostatic mechanisms. All these denominators of aging have important repercussions on cellular metabolism. Here, we describe the links between each hallmark of aging and metabolic perturbations, discuss current strategies to manipulate metabolism for increasing healthspan and lifespan, and elaborate on the major threat posed to public health in the developed world, i.e., the incipient "westernization" of lifestyle.

Aging complicates the maintenance of cellular and organismal metabolic homeostasis, hence favoring an imbalance in metabolic landscape that self-amplifies and eventually becomes clinically manifest. Thus, anti-aging interventions such as calorie restriction may operate in the context of a metabolic reprogramming that (1) ensures efficient nutrient utilization and (2) enhances stress resistance. Although such a metabolic reprogramming may be extremely broad and hence difficult to modulate pharmacologically, it may be subjected to some unifying principles. In particular, the signal-transduction cascades and metabolic circuitries rewired in the course of aging may operate in the context of a limited number of modules that redistribute nutrients and other resources from anabolism to non-toxic catabolism, hence favoring homeostasis preservation.

Our current knowledge on the metabolic manipulations that may improve health in the elderly and hence extend longevity are still in their infancy, although there is no doubt that a combination of regular exercise and appropriate diet can delay the onset and progression of all the hallmarks of aging. Formulating dietary recommendations is complicated, and personalized advice from a nutritionist may be recommendable in some situations. Nonetheless, we surmise that an increase in food-free intervals, a reduction in overall caloric and animal protein intake, as well as a general shift from health-compromising food to a Mediterranean diet rich in fibers and complex carbohydrates may have sizeable anti-aging effects, especially when combined with regular physical activity.

Link: http://www.cell.com/...8674(16)30981-3


View the full article at FightAging

#5 Darryl

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Posted 16 August 2016 - 02:21 PM

Most of the Hallmarks of Aging authors are back with another review in Cell.

 

López-Otín, C., Galluzzi, L., Freije, J.M., Madeo, F. and Kroemer, G., 2016. Metabolic Control of Longevity. Cell, 166(4), pp.802-821.

 

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#6 albedo

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Posted 21 August 2016 - 01:46 PM

Thank you for posting that Darryl. I had some difficulty to find it after I learned about it looking at the last Rejuvenation Biotechnology RB2016 conference supported by SENS at Buck. The wonderful review paper was quoted by the first keynote Pinchas Cohen (see min 19:33 of the reply) for those interested. The Hallmarks were 9 though also in 2013 if i recollect well (see here). Very interesting at RB2016 also the Judith Campisi's talk on senescent cells (1:27:30 of the reply).



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#7 albedo

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Posted 28 June 2017 - 12:23 PM

Nice to hear Aubrey about this great paper at min 20:12 here: http://www.ideacity....ical-longevity/






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