Naked mole rats defy the biological law of aging | Hacker News Reader

Naked mole rats defy the biological law of aging

sciencemag.org

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Study: Naked mole-rat mortality rates defy Gompertzian laws by not increasing with age

Citation: J Graham Ruby; Megan Smith; Rochelle Buffenstein; eLife 2018.

Link: https://doi.org/10.7554/eLife.31157

DOI: 10.7554/eLife.31157

Abstract: The longest-lived rodent, the naked mole-rat (Heterocephalus glaber), has a reported maximum lifespan of >30 years and exhibits delayed and/or attenuated age-associated physiological declines. We questioned whether these mouse-sized, eusocial rodents conform to Gompertzian mortality laws by experiencing an exponentially increasing risk of death as they get older. We compiled and analyzed a large compendium of historical naked mole-rat lifespan data with >3000 data points. Kaplan-Meier analyses revealed a substantial portion of the population to have survived at 30 years of age. Moreover, unlike all other mammals studied to date, and regardless of sex or breeding-status, the age-specific hazard of mortality did not increase with age, even at ages 25-fold past their time to reproductive maturity. This absence of hazard increase with age, in defiance of Gompertz’s law, uniquely identifies the naked mole-rat as a non-aging mammal, confirming its status as an exceptional model for biogerontology.

There are a wide variety of life courses exhibited in the natural world, when plotting mortality risk over time. The human early start on an exponential increase is just one of them. Flies that reach a mortality risk plateau in late life is another - they just stop aging, they don't get any more damaged in ways that cause mortality than they already are. More complex organisms don't seem to exhibit this phenomenon, but the data for humans is pretty sparse at the ages of interest.

Naked mole rats and humans age for the same underlying reasons, the same types of accumulated damage. The difference in outcomes in terms of the shape of the mortality curve no doubt has to do with quality of repair mechanisms and resilience to particular forms of damage. Naked mole rats have less error-prone DNA replication, repair, and protein manufacture processes, a lack of lingering senescent cells pumping out inflammatory and destructive signals, a mitochondrial composition that is more resilient to oxidative stress (and they have plenty of oxidative damage, judging from the usual markers, they just seem to shrug it off; it doesn't cause further problems). The net result of this is that they do pretty well then fall off a cliff at the end.

It is interesting to speculate on what the cliff might be, a high threshold of damage needed to break an important repair mechanism, or a slowly accumulating form of damage that only really hurts the mole-rat at high levels, for example, but this is probably not very relevant to human medicine.

We know why humans age. We know what the damage is. We don't need to poke around in other species for further illumination in order to make progress towards rejuvenation - we won't learn anywhere near as much as we will from selective repair of the damage in humans or in mammals that are similar to humans. We don't need to improve human damage repair systems (comparatively hard) when we can repair damage (comparatively easy). It clearly takes a few decades for pathological levels of damage to arise, which gives plenty of time to deal with it through periodic applications of therapy, given a working repair biotechnology.

The comparative biology of aging is pure science, unlikely to produce meaningful applications of medicine when compared with other courses of action.

IANAGB and your meta-explanation makes total sense _but_ I'm given to believe that improving human damage repair systems would require gene therapy and this is becoming an easier and easier technique over time–isn't this what powers a lot of medical breakthroughs now? Am I wrong in believing this? Are you definitively asserting that repairing damage is going to be comparatively simpler than improving damage repair systems for the foreseeable future?

Only some of the damage repair methods require gene therapy, and in the case of allotopic expression to work around mitochondrial damage that is already demonstrated in human trials by Gensight.

You should look over the linked sub-pages here for an overview of the types of damage and approaches to repair.

http://www.sens.org/research/introduction-to-sens-research

I'd be more concerned about stem cell replacement therapies and lipofuscin removal as categories than anything requiring gene therapy, since in both cases there are a lot of targets and a lot of work to do.

For things like senescent cells and glucosepane cross-links, small molecule therapies will work (and already exist in the former case). In fact all targeted cell killing and specific molecule breakdown needs can probably be addressed sufficiently well via pharmaceuticals for a first generation effort.

Thanks for the pointers.

I've read that humans are the same, they quit "aging" after age 110 or so. At that point the probability of dying in the next year is roughly 50%, and doesn't increase beyond that age.

Granted it appears the number of people to live so long is only a few hundred. And if halving each subsequent year, not a huge sample size.

The statistics and probability are improperly applied to this situation, and fail to accurately model reality.

The numbers are taken as abstractions and untethered from the complex subsystems that generate the results. This decoupling eliminates any understanding of the underlying principles at work.

Human tissues are organized into organs that eventually fail. When you put the tables and figures away, and look at the actual centenarians themselves, there’s no expectation that those people’s organs will continue on an endless plateau of static operation without further incident, in an endless streak of winning coin flips.

The reality is that life at that age isn’t abstract coin flips, there’s definite decline lurking in the background. Externalities like microbial illness could be modeled as coin flips (does the individual catch the flu this year?), but internal deterioration is still a systemic function with a graded slope that varies from person to person.

That declining slope could be altered with transplants, but eventually the brain gets involved, and we lack the metaphysical and philosophical tools to argue about when a zombie robot brain transplant might mean animate brain death or the living exchange and passing of one distinct individual for wholly another living mind.

Good point. So the cause is more likely that the distribution of the underlying genetic code that determines max life span for an individual is what follows the Poisson distribution at the tail end, rather than any individual's own aging process (or apparent statistical lack thereof). That makes more sense.

The number of data points is a bit misleading. Unless I am interpreting it wrongly, it looks like less than 100 rats were actually used to look at the hazard rate? Most of the ~3000 rats were censored because they moved/euthanized for experiments?

I'm not arguing with their methods but I think there is an alternative explanation to their data: naked mole rats might still have gompertzian aging but with an exponent that is low enough to not show up at the age of 30 or so. Humans also don't display any signs of biological aging up to the age of 30, but around 70 everything starts to fall apart. My point is, until we have a decent sample size of 70+-year-old naked mole rats, we won't know.

Only about 10% (469/3848) of their data had actual birth dates and death dates.[1] That looks like this: https://image.ibb.co/bJLq4G/lspan.png

[1] https://elifesciences.org/articles/31157/figures#supp1

EDIT:

I'm not sure what to conclude from that but think the clean data only should have been in the paper...

Is there any good sequence of moocs to let an engineer go from mostly-forgotten high school biology and chemistry to understanding the cutting edge of aging research?

Because there is no biological law of aging. There is only a collection of biological accidents.

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