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Review on What's Known about Aging and What To Do About It

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There is a new paper out [1] (popular account) that seems to me to do a pretty good job summarizing what we know about the different causes of aging. They have the same perspective as Aubrey, Michael & SENS - namely that at its root aging is a result of metabolic damage accumulation. But they appear to have a slightly different taxonomy than Aubrey's "7 deadly causes", although I'll leave it to Michael to map between the two. Here is there graphic showing the "Hallmarks of Aging":




One thing that jumped out at me (and that I've highlighted above in yellow) was the role peroxisome proliferator-activated receptor-gamma coactivator 1alpha (PGC1α) appears to play in the various hallmarks of aging. In fact, a drop in PGC1α signalling is implicated in four of the nine hallmarks of aging. This interests me, because PGC1α promotes mitochondria biogenesis, and is upregulated by cold exposure [2], as we've seen many times on the cold exposure thread.


Sadly, the authors don't mention cold exposure as a potential means to ameliorate the aging process. Instead they focus on CR, amino-acid restriction, CR-mimetics, time-restricted feeding, and exercise as the most promising longevity interventions. Oh well, someday the benefits of cold exposure will be more widely recognized.


Overall it's an fascinating paper covering both the mechanisms of aging and (some of) the best ideas we have for what can be done about it today.





[1] Cell 166, August 11, 2016


Metabolic Control of Longevity


Carlos Lo´ pez-Otı´n,1,* Lorenzo Galluzzi,2,3,4,5,6,7 Jose´ M.P. Freije,1 Frank Madeo,8,9 and Guido Kroemer
Several metabolic alterations accumulate over time along with a reduction in biological fitness, suggesting
the existence of a ‘‘metabolic clock’’ that controls aging. Multiple inborn defects in metabolic
circuitries accelerate aging, whereas genetic loci linked to exceptional longevity influence metabolism.
Each of the nine hallmarks of aging is connected to undesirable metabolic alterations. The
main features of the ‘‘westernized’’ lifestyle, including hypercaloric nutrition and sedentariness,
can accelerate aging as they have detrimental metabolic consequences. Conversely, lifespan-extending
maneuvers including caloric restriction impose beneficial pleiotropic effects on metabolism.
The introduction of strategies that promote metabolic fitness may extend healthspan in humans.
PMID: Not available
[2] Adv Physiol Educ. 2006 Dec;30(4):145-51.

PGC-1alpha: a key regulator of energy metabolism.

Liang H(1), Ward WF.

Author information:
(1)Department of Cellular and Structural Biology, Audie Murphy Veterans
Administration Medical Center and University of Texas Health Science Center, San
Antonio, Texas 78229-3900, USA.

Peroxisome proliferator-activated receptor-gamma coactivator (PGC)-1alpha is a
member of a family of transcription coactivators that plays a central role in the
regulation of cellular energy metabolism. It is strongly induced by cold
exposure, linking this environmental stimulus to adaptive thermogenesis.
PGC-1alpha stimulates mitochondrial biogenesis and promotes the remodeling of
muscle tissue to a fiber-type composition that is metabolically more oxidative
and less glycolytic in nature, and it participates in the regulation of both
carbohydrate and lipid metabolism. It is highly likely that PGC-1alpha is
intimately involved in disorders such as obesity, diabetes, and cardiomyopathy.
In particular, its regulatory function in lipid metabolism makes it an inviting
target for pharmacological intervention in the treatment of obesity and Type 2

DOI: 10.1152/advan.00052.2006
PMID: 17108241

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  • 2 weeks later...

From the same paper is a paragraph which reminds me a lot of the description of what goes goes wrong metabolically in my disease SBMA in the July paper showing a switch from glycolytic to oxidative muscle fiber in SBMA knock-in mice that are rescued by a high fat diet.  I'm also increasingly convinced NAD depletion is a major factor as each time I significantly boost my dosage of the precursors nicotinic acid and nicotinamide riboside I have a measurable boost in physical performance.


Some of the best-studied human progerias, ataxia telangiectasia, Cockayne syndrome, and xeroderma pigmentosum, are
disorders of nucleotide excision repair characterized by severe neurodegeneration. These diseases are accompanied by the
hyperactivation of poly(ADP-ribose) polymerase 1 (PARP1), a nicotinamide adenine dinucleotide (NAD)-dependent enzyme
involved in DNA repair. PARP1 hyperactivation leads to NAD depletion, hence inhibiting the NAD-dependent deacetylase sir-
tuin 1 (SIRT1) (Fang et al., 2014). These events lead to mitochondrial abnormalities, including reactive oxygen species (ROS)
generation, increased transmembrane potential, and limited mitochondrion-selective autophagy (mitophagy), all of which
can be rescued in mice by PARP1 inhibition or external supply of the NAD precursor nicotinamide riboside (Fang et al., 2014;
Scheibye-Knudsen et al., 2014).
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  • 1 month later...

This free full text link doesn't seem to be free full text anymore (at least not for me). I wonder if it was only temporary (or you have some extra access). But thanks for the heads-up anyway---looks worth a read sometime.


The last decent survey article I saw on aging was also from Cell (2 years ago):

The Search For Antiaging Interventions, de Cabo et al

DOI: http://dx.doi.org/10.1016/j.cell.2014.05.031


BTW, if anyone is interested in longer book-length (but detailed biology, not just lay-audience-targeted) treatments of aging, besides of course Ending Aging by Aubrey and Michael (which is now quite old), I compiled a short list of more recent books:

I haven't actually read these, so can't recommend which are best. The first half or so of The Longevity Dividend is good. I know Campisi & Lithgow are good and expect the book they co-edited to be excellent, though it's purchase link on geron.org (at the above link) seems to be broken right now---not sure what happened there.



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