
The Hallmarks of Aging (2013) - evo_9
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3836174/
======
jz_
Related to this is the Rejuvenation Roadmap [https://www.lifespan.io/the-
rejuvenation-roadmap/](https://www.lifespan.io/the-rejuvenation-roadmap/)
which is an attempt to catalog current research efforts for interventions
along the lines of the hallmarks.

~~~
LinuxBender
Are there any facilities that map all or most of those areas to full
diagnostics of a person and try to mitigate the aging effects from chronic
issues?

The reason I ask is that hospitals only deal with acute issues, based on my
experience and seldom have the time, technology, experience or willingness to
diagnose chronic issues, much less reverse them.

The closest to this I have found are functional medicine clinics, but they
don't even scratch the surface of most of the areas your link mentions. Most
of them just look at diet, genetics and gut health.

~~~
jz_
I'll answer the question two parts:

> Are there any facilities that map all or most of those areas to full
> diagnostics of a person

Not exactly, it's all very much an underdeveloped area of research. Biomarkers
of biological aging are still being developed, and what has to happen is
"translation" into the clinic before any hospital or medical practice can
really claim to offer treatment.

On mapping/diagnosing:

Although telomere attrition is a hallmark, leukocyte telomere length has long
been criticised as unreliable, which is popularly available as direct to
consumer testing companies are capitalising on ignorance.

[https://onlinelibrary.wiley.com/doi/abs/10.1002/ajhb.22906](https://onlinelibrary.wiley.com/doi/abs/10.1002/ajhb.22906)

[Telomeres, Aging and Exercise: Guilty by Association?
(2017)]([http://www.mdpi.com/1422-0067/18/12/2573](http://www.mdpi.com/1422-0067/18/12/2573))

[Salk scientists find that for stem cells to be healthy, telomere length has
to be just right (2016)]([http://www.salk.edu/news-release/goldilocks-effect-
aging-res...](http://www.salk.edu/news-release/goldilocks-effect-aging-
research/))

['This test is garbage': Experts in telomere biology and former employees
allege that a Silicon Valley startup gives bogus 'cellular ages' based on a
flawed blood test]([https://www.thisisinsider.com/silicon-valley-telomere-
blood-...](https://www.thisisinsider.com/silicon-valley-telomere-blood-
test-2018-9))

I think the current more promising biomarker is epigenetic age:

[https://www.nia.nih.gov/news/epigenetic-age-estimated-
change...](https://www.nia.nih.gov/news/epigenetic-age-estimated-changes-dna-
methylation-predicts-mortality)

[https://en.wikipedia.org/wiki/Epigenetic_clock#Properties_of...](https://en.wikipedia.org/wiki/Epigenetic_clock#Properties_of_Horvath's_clock)

Horvath spoke at a conference last year recorded here:
[https://www.youtube.com/watch?v=uw1J0UqWSjo](https://www.youtube.com/watch?v=uw1J0UqWSjo)

Direct to consumer testing:
[https://www.mydnage.com/services](https://www.mydnage.com/services)

The high level view is that whatever rejuvenation therapy versus one or more
hallmarks does, should also reverse epigenetic age to validate it.

On a less theoretical level, any intervention would also have functional
outcomes that reflect things like cognition, strength, balance, immune system
function, and follow up monitoring for disease incidence and decline.

In terms of reversal, again - we have to wait for things to progress through
the stages of clinical trials. No one wants to be pushing unverified snake
oil, given the long history of that around aging and health.

part two of your question:

> and try to mitigate the aging effects from chronic issues?

The only consolation currently I think is that for those that can exercise,
should based on what's known about the benefits:

* [Aging Hallmarks: The Benefits of Physical Exercise (2018)]([https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5980968/](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5980968/))

* [Exercise Attenuates the Major Hallmarks of Aging (2015)]([https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4340807/](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4340807/))

> Most of them just look at diet

Some biogerontologists do think that it's possible to slow the effects of
aging with short dietary intervention, such as Valter Longo, who designed a
5-day low protein (as protein inhibits autophagy) calorie restricted diet
based on animal research and success in humans. The 'Fasting Mimicking Diet'
or FMD. Before anyone asks - no it has not been validated against epigenetic
age. That would be a good line of inquiry. Yes, anyone can do it with basic
ingredients from a supermarket. There's a subreddit for it:
[https://www.reddit.com/r/FMD](https://www.reddit.com/r/FMD)

Selected research on fasting and the FMD:

Longo and Mattson, 2014. [Fasting: molecular mechanisms and clinical
applications]([https://www.sciencedirect.com/science/article/pii/S155041311...](https://www.sciencedirect.com/science/article/pii/S1550413113005032)).
Cell metab, 19(2), pp.181-192. Cheng et al, 2014. [Prolonged fasting reduces
IGF-1/PKA to promote hematopoietic-stem-cell-based regeneration and reverse
immunosuppression]([https://www.sciencedirect.com/science/article/pii/S193459091...](https://www.sciencedirect.com/science/article/pii/S1934590914001519)).
Cell stem cell, 14(6), pp.810-823. Brandhorst et al, 2015. [A periodic diet
that mimics fasting promotes multi-system regeneration, enhanced cognitive
performance, and
healthspan]([https://www.sciencedirect.com/science/article/pii/S155041311...](https://www.sciencedirect.com/science/article/pii/S1550413115002247)).
Cell metab, 22(1), pp.86-99. Longo and Panda, 2016. [Fasting, circadian
rhythms, and time-restricted feeding in healthy
lifespan]([https://www.sciencedirect.com/science/article/pii/S155041311...](https://www.sciencedirect.com/science/article/pii/S1550413116302509)).
Cell metab, 23(6), pp.1048-1059. Di Biase et al, 2016. [Fasting-mimicking diet
reduces HO-1 to promote T cell-mediated tumor
cytotoxicity]([https://www.sciencedirect.com/science/article/pii/S153561081...](https://www.sciencedirect.com/science/article/pii/S1535610816302653)).
Cancer cell, 30(1), pp.136-146. Choi et al, 2016. [A diet mimicking fasting
promotes regeneration and reduces autoimmunity and multiple sclerosis
symptoms]([https://www.sciencedirect.com/science/article/pii/S221112471...](https://www.sciencedirect.com/science/article/pii/S2211124716305769)).
Cell rep, 15(10), pp.2136-2146. Wei et al, 2017. [Fasting-mimicking diet and
markers/risk factors for aging, diabetes, cancer, and cardiovascular
disease]([http://l-nutra.com/wp-content/uploads/2017/02/science-
transl...](http://l-nutra.com/wp-content/uploads/2017/02/science-
translational-medicine-february-2017.pdf)). Sci trans med, 9(377), p.eaai8700.
Cheng et al, 2017. [Fasting-mimicking diet promotes Ngn3-driven β-cell
regeneration to reverse
diabetes]([http://www.celprogen.com/uploads/product/14902320845.pdf](http://www.celprogen.com/uploads/product/14902320845.pdf)).
Cell, 168(5), pp.775-788. Guidi N, Longo VD, 2018 [Periodic fasting starves
cisplatin-resistant cancers to
death]([https://www.ncbi.nlm.nih.gov/pubmed/29875131](https://www.ncbi.nlm.nih.gov/pubmed/29875131))

Fontana et al, 2013. [Dietary protein restriction inhibits tumor growth in
human xenograft models of prostate and breast
cancer]([https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3926840/](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3926840/)).
Oncotarget, 4(12), p.2451. Mirzaei et al, 2014. [Protein and amino acid
restriction, aging and disease: from yeast to
humans]([https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4254277/](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4254277/)).
Trends Endocrin Metab, 25(11), pp.558-566. Levine et al, 2014. [Low protein
intake is associated with a major reduction in IGF-1, cancer, and overall
mortality in the 65 and younger but not older
population]([https://www.sciencedirect.com/science/article/pii/S155041311...](https://www.sciencedirect.com/science/article/pii/S155041311400062X)).
Cell metab, 19(3), pp.407-417. Shim and Longo, 2015. [A protein restriction-
dependent sulfur code for
longevity]([https://www.sciencedirect.com/science/article/pii/S009286741...](https://www.sciencedirect.com/science/article/pii/S009286741401633X)).
Cell, 160(1-2), pp.15-17. Mirzaei et al, 2016. [The conserved role for protein
restriction during aging and
disease]([https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4807119/](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4807119/)).
Curr op clin nut metab care, 19(1), p.74. Song et al, 2016. [Association of
animal and plant protein intake with all-cause and cause-specific
mortality]([https://jamanetwork.com/journals/jamainternalmedicine/fullar...](https://jamanetwork.com/journals/jamainternalmedicine/fullarticle/2540540)).
JAMA in med, 176(10), pp.1453-1463. Wei et al, 2017. [Fasting-mimicking diet
and markers/risk factors for aging, diabetes, cancer, and cardiovascular
disease]([https://www.ncbi.nlm.nih.gov/pubmed/28202779](https://www.ncbi.nlm.nih.gov/pubmed/28202779))

~~~
LinuxBender
Thankyou for the in depth and detailed answer. I was afraid that such research
has not found its way into any clinics yet. In terms of exercise, I walk about
5 miles a day on weekdays.

In terms of protein restriction, I have read up on that as well, since I had
been repairing my gut from significant damage. One of my primary concerns was
that I would be providing everything that cancer cells need to grow and
spread. To compensate for the potential Metastasis, I implemented things into
my diet that are said to inhibit the spread, such as Curcumin and aged garlic
extract. Only time will tell I suppose. I am reaching the point where I can
likely defer the amino acids for 2 out of 4 weeks at a time. Beyond that and
soy, I don't get excess protein.

Thankyou for the links. I will read up on the reddit posts later today.

------
reasonattlm
From the SENS point of view [1] a number of the Hallmarks are downstream
consequences of the causes of aging; e.g. epigenetic alterations are a
reaction to molecular damage. Attempting to use those hallmarks as a place to
intervene is doomed to achieve marginal benefits at best. You can't cure an
age-related disease by patching over its late consequences.

Aging is a spreading tree of cause and consequence, emerging from a few root
cause forms of damage. Intervene at later branchings in the tree, and you
cover ever fewer downstream harms. It would be like trying to prevent a
complicated iron sculpture from collapsing by propping up a few pieces here
and there rather than by de-rusting/rustproofing the whole thing. Intervention
as close to the root causes as possible is the only effective way forward,
given how challenging it is achieve anything in medical biotechnology.

At the time the Hallmarks of Aging was published, it was noted for completely
failing to reference any of the existing SENS literature, despite including
some of the SENS line items such as senescent cell accumulation. The Hallmarks
- and the related Seven Pillars of Aging [2] that seems to be less well
promoted - would clearly not exist without more than a decade of aggressive
advocacy within the scientific community for SENS and the treatment of aging,
but the Hallmarks authors chose to behave as though that prior work never
happened.

[1]: [https://www.sens.org/research/introduction-to-sens-
research](https://www.sens.org/research/introduction-to-sens-research)

[2]: [https://www.fightaging.org/archives/2014/11/the-seven-
pillar...](https://www.fightaging.org/archives/2014/11/the-seven-pillars-of-
aging/)

~~~
yholio
Is it really plausible to think that stopping cell and tissue degeneration is
synonymous with curing ageing and transforming the human body into a perpetual
self-repairing machine?

We have evolved to acomodate these senescence mechanisms in various way, so
shouldn't we expect that halting them should have unforeseeable consequences
that evolution couldn't have prepared against? Shouldn't we expect the genome
itself to have embedded within it some notion of the organism's age ? (as
opposed to a limited development to a mature, final state that could go on
forever in the absence of celular ageing)

I'm thinking, for example, at the limited number of female gametes available
at the start of life. There was never a need to evolve regenerating gametes so
the reproductive lifetime of an immortal woman is still limited. How many such
innate limitations could there be in a genome after a billion years of
evolution from mortal organisms?

~~~
tormeh
No, but is that so important? If we can fix cell and tissue degeneration we're
likely to prolong life span and improve quality of life dramatically. We can
do the rest when we get there.

~~~
yholio
It's certainly a necessary condition to prolong life but I would hold the
"dramatic" epithet until we get there.

Once down the rabbit hole, we might well encounter an endless barrage of other
genomic self destruct clocks.

------
vark90
A somewhat relevant question: what is a good way to get into longevity
research/research support for a software engineer with a degree in optical
engineering, who recently started refreshing college math?

~~~
dekhn
focus on microscopy. if you have an optical engineering degree you could learn
how to build a modern microscope using thorlabs components. then find some
labs that need a scope person.

you shouldn't expect, with your academic pedigree and work experience, to be
able to pick up enough biology to be truly useful for deep discovery. You can
help out writing code, but don't expect to be able to design, run, and analyze
the results of an experiment. In biology, it takes decades to be able to judge
the results (very different from computer science and machine learning).

~~~
p1esk
There's good probability that within next 10 years some/most of that work
"judging results" will be automated through machine learning.

~~~
throwawaymath
Why do you say that?

~~~
dekhn
Well, I can speak to this since I work for a company that does this. The
improvement in microscope image analysis by computers in the past 5 years has
been amazing. If the trajectory continues, I would say that 25% of image
analysis will be automated using DNNs and other machine learning techniques.

Areas where it won't work: any time you have new image data that doesn't
resemble what the networks were trained on. In fact, most people in the field
recommend training on and running inference on a single microscope and if you
change scopes, you have to retrain your model! Obviously data augmentation has
a lot to contribute there but there a ton of challenges.

I've actually proposed building a warehouse-scale microscopy facility within a
couple miles of amazon or google data center with full realtime reinforcement
learning loop. If you have hundreds of near-identical scopes collecting the
same data, you can train over the variation.

------
mirimir
It's pretty obvious that accumulation of genetic and epigenetic errors -- bit
rot -- is a major factor.

But there's also a developmental issue. Neoteny played a substantial role in
human evolution. And as people get older, they tend to look more and more like
adult "prehuman" primates. Bushy eyebrows. Hair on the ears.

~~~
skookumchuck
So that's why people have started calling me "Thag".

