
Naked mole rats defy the biological law of aging - nabla9
http://www.sciencemag.org/news/2018/01/naked-mole-rats-defy-biological-law-aging
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randomdrake
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](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.

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reasonattlm
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.

~~~
igravious
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?

~~~
reasonattlm
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](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.

~~~
igravious
Thanks for the pointers.

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daxfohl
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.

~~~
mindFilet
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.

~~~
daxfohl
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.

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daemonk
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?

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fallingfrog
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.

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nonbel
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](https://image.ibb.co/bJLq4G/lspan.png)

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

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tw1010
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?

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

