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The Hallmarks of Aging (2013) (nih.gov)
175 points by evo_9 on Jan 4, 2019 | hide | past | web | favorite | 38 comments

Related to this is 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.

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.

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.


[Telomeres, Aging and Exercise: Guilty by Association? (2017)](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...)

['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-...)

I think the current more promising biomarker is epigenetic age:



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

Direct to consumer testing: 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/)

* [Exercise Attenuates the Major Hallmarks of Aging (2015)](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

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...). 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...). 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...). 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...). 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...). 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...). 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...). 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). 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)

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/). 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/). 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...). 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...). 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/). 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...). 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)

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.

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

[2]: https://www.fightaging.org/archives/2014/11/the-seven-pillar...

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?

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.

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.

Are you saying that they did not cite any of the papers on this list [0]? Or that they didn't cite the pop-sci books and articles? I don't know, just curious. (I think the former would be bad, but the latter would be more OK.)

[0] https://www.sens.org/research/publications

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?

Try to make contact with grad students and postdocs working in research groups that align with your aims. Find out what the most annoying/repetitive parts of their research are and see if you can think of improvements matched to your skill set. (This could be as simple as joining a Facebook group, forum, or mailing list, and reading what people complain about.) It could be something you can improve with software alone. I'm guessing that there are unmet equipment needs too. PIs are not always incentivized to care about improving the labor efficiency of their underlings.

An uncle of mine got his PhD and then after his postdoc spent the rest of his working life helping other researchers at his university build equipment to support experiments. He had skills with machining and design that most of his colleagues lacked. Much of hands-on scientific research can be improved by some not-too-complicated piece of equipment, but that equipment isn't available off the shelf yet. Some researchers are lucky enough to be supported by people like my uncle, or already have skills like my uncle. Most biological researchers aren't also engineers. You might advance the productivity of biological research, maybe even do well financially if you design something that a company like Millipore ends up acquiring.

Tedious pipetting work used to be a major waste of time in some kinds of biological research. There are commercial robots for that now. What's the next most tedious thing that could be improved with good tooling? I don't know, but you might want to see if you can find out.

EDIT: I'm suggesting that you look for opportunities regarding experimental research instead of pure software because I'm not sure current experimental data is good/abundant enough. I was peripherally involved with an academic "proteomics" software effort more than a decade ago (is that still a trendy thing?) and my experiences led me to believe that experimental reproducibility and throughput needed to improve before it was worth focusing on software. I also hear biologists gripe about slow, poorly reproducible cell experiments in places like the comments on Derek Lowe's blog.

My personal hobby is computational chemistry but if I wanted to make a real impact on chemistry I think it would have to relate to instrumentation or tooling for bench chemists. Chemistry and especially biology are too complicated for theoretical/computational approaches to contribute much without collaborating with experimentalists.

> too complicated

More specifically, the difficulty is in developing computationally efficient models (i.e. algorithms that could be used on today's computers) - vs. just using computational methods of quantum mechanics, which in theory should be able to model anything that consists of atoms but in practice turns out to be too computationally intensive.

There are molecular mechanics/molecular dynamics methods that use only classical physics ("ball and spring" models). That's part of computational chemistry.

To elaborate on your comments, most of computational chemistry does use quantum mechanical models, and there are indeed difficult problems with computational intensity. Basic quantum chemical methods start with a big-O time complexity of O(N^4). The "gold standard" of computational chemistry, CCSD(T), is O(N^7). It is the worst-scaling method that still sees routine use.


An "exact" [1] approach to electronic structure calculations, full configuration interaction, scales as O(N!) -- yes, factorial. Not surprisingly, the size of systems tractable via FCI has not grown much in 30 years even as computers have grown much faster.

There is indeed a lot of work applied developing efficient approximations to the "exact" quantum mechanical solution, and to eking out more constant-factor improvements from existing algorithms.

There's also a lot of work on taking electronic structures, available from various methods, and deriving familiar chemical properties from them. Things like NMR spectra, Raman spectra, pKa, melting point, aqueous solubility...

Measuring properties of bulk condensed-phase matter in the lab is easy but it's hard in simulation. Something "basic" like melting point is very hard to derive from ab initio calculations. On the other hand, properties that require expensive equipment to measure, like NMR spectra, are comparatively easy to calculate.

[1] Terms and conditions apply. Consult Helgaker et al. "Molecular Electronic‐Structure Theory" for details.

Our mission at Spring is to accelerate the discovery of therapies for age related diseases. Machine learning is a core part of our approach and we're building a close-knit team of scientists and engineers. If you're interested, check out our job openings [1]. We also just raised an A round with support from some fantastic folks [2], including Laura Deming who put out this great FAQ on the space if you haven't already seen it: https://www.ldeming.com/longevityfaq/

[1] https://www.springdisc.com/#careers

[2] https://medium.com/spring-discovery/with-18-million-in-new-f...

Start emailing people that write papers you like about aging and tell them how you can help their group and ask for a job. You might be surprised. That's pretty much how my boss hires people. I don't work in aging but in cancer research in academia, but I doubt it is that different.

I recently started my lab at UC Berkeley studying aging and longevity using genomics and computational approaches. https://www.sudmantlab.org Feel free to drop me a line if you're interested in getting involved!

Cheers, Peter

Get a very high paying job and then donate your money to research. If you want to get involved with the research then just start giving the money to the researcher you want without strings (no grant or report writing). Then use this as a chance to chat to the researchers about the research.

We can't really do much about ageing until we solve cancer as ageing is the evolutionary original anti-cancer system.

since many people progress to late 80s and 90s without cancer, it's likely we can increase longevity (not immortality) without addressing cancer as a dependency first. After all, the greatest advances in mortality came from reducing child mortality and addressing infectious diseases that lead to long-term health effects.

Most people in their 80s and 90s have cancer, but thanks to ageing the cancer is very slow growing so they die of something else. For example, in men the percentage probability of having prostate cancer is equal to your age yet few men die of prostate cancer.

There are some mutations in people that slow ageing at the expense of increasing the cancer rate. There is a very interesting one from Brazil where a mutation in the p53 gene has this exact mechanism [0].

0. https://youtu.be/URKJ7LLXc3E (you can skip the first 5 minutes - the relevant part is around minute 15).

I think you mean, most people in their 80s and 90s have benign tumors, not cancer.

Heart disease research investments would likely have equal or superior payoffs to cancer research investments.

No they have full non-benign cancers, they are just so slow growing that the person with them normally dies of something else first although plenty of people in their 80s and 90s die of cancer.

Yes the life expectancy increase from curing cancer is only around 2 years, but it is the essential first step to doing something major about ageing.

non-benign cancer = invasive tumor. people with invasive tumors rarely die of other causes which are not correlated.

anyway, I don't think anybody in the serious scientific community believes that a cancer-only research program would have a huge impact on longevity and instead, most people advocate for a portfolio with roughly 70% spent across cardiovascular and cancer, and the rest on other causes.

Heart disease and cancer are symptoms of aging, not causes. Why would we treat the (very many) symptoms individually if we can treat the cause?

do you know the cause of aging? Nobody does. Instead, what we do is address the symptoms, because that generally leads to longevity and higher quality of life in older years. That's what the medical system is dedicated to doing. I say this with full knowledge that my friends who work at Buck Institute of Aging are working on the underlying causes of aging and they've all said it's better to focus on treating those symptoms.

BTW what you've said is also fairly philosophical. It would be completely correct to say that heart disease is a cause of aging, under a reasonable definition of aging.

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).

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

Why do you say that?

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.

Plus you get lab snacks if you go this route. If you order both from the US and European warehouses, you even get a wider variety of snacks.

I live for thorsnacks and was trying to get a thorough from my coworker but there is too much demand

> what is a good way to get into longevity research/research support

The Longevity Investor Network [1] might be of interest. (Disclaimer: I have donated, and actively consider investing, through them.)

[1] https://www.leafscience.org/longevity-investor-network/

Talk to the folks at SENS and ask how you can help. Or, go apply to one of the companies here: https://www.methuselahfund.com/

(Disclaimer: I'm a regular donor to the former and an investor in the latter, in both cases because I believe in their mission.)

I'm reading Aubrey de Grey's book Ending Aging right now. I'm finding it to be a good read and a great introduction to his approach, SENS (http://www.sens.org).

Not directly related, but

I would look into optical imaging and biophotonics there are many exiting emerging technologies that may revolutionize research (into longevity among others) and healthcare in general. Optical coherence tomography for example.

I contacted lifespan.io with a similar question and they suggested I'd join their Discord server to have a deeper discussion about how to help.

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.

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

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