Hallmarks of aging – time for a paradigm shift?

If you’re like me, then possibly your first introduction to the field of biogerontology is the 2013 review articles “The hallmarks of aging” by Lopez-Otin et al. This most cited review in the field of aging defines common denominators of aging in different organisms into 9 different hallmarks and is a pretty common reference point for the field.

I’ve always liked the hallmarks as an introduction to the field, so much so that I described the hallmarks in some of my earliest videos. Speaking of my earliest videos, given that it’s almost my 2-year birthday on YouTube, I’d thought I’d revisit the hallmarks of aging given that there has been some recent criticism on them suggesting that maybe we should start to look beyond them.

TIMESTAMPS
Intro - 00:00
Scientific Paradigms (Thomas Kuhn) - 01:10
Hallmarks of aging - 03:00
Hallmarks of cancer - 06:20
Issues with the hallmarks - 08:20
How to improve the hallmarks - 09:50
My thoughts - 11:00

References:
Gems, D.; de Magalhães, J.P. The Hoverfly and the Wasp: A Critique of the Hallmarks of Aging as a Paradigm. Preprints 2021, 2021050310 (doi: 10.20944/preprints202105.0310.v1).

[LifespanNews]

This was a great video on the importance of paradigms in science and an interesting discussion about the hallmarks! Well done! We were very happy to work with you on this topic :)

[BrentNally]

Great video as always! We definitely need consensus on how to solve the human aging problem ASAP so there’s much work to be done 😬

[kral]

So glad to see Aubrey's work in this channel! His main criticism of the Hallmarks of Aging paper has been that there is 0 mention of Extracellular Matrix Stiffening (Advanced Glycation End Products that form when sugar interacts with proteins and creates crosslinks that are problematic when not cleaved, main one in Humans being Glucosepane which accounts for %90 of AGE's at least in the skin, SENS Foundation spun-off a company called Ravel Pharmaceuticals that have made some but appreciable progress in the last few years.).
Also quite surprised that you haven't read his book yet as it was the first book that i read when i for the first time got serious and went down the rabbit hole of aging last year :D
He has infamously been giving a time line for the Longevity Escape Velocity (which he has lowered down to just 15 years with %50 now!) but he also states that there is a %10 chance that we won't reach L.E.V in 100 years which would most likely be because of a major global catastrophe or if the Types of Damage table (or Hallmarks of Aging it is called after that paper) doesn't stand the test of time. Although i have seen him on Quora say that he is a little more confident about the %50 chance and even the %10 chance of not happening is closer to %5.

[ssiddarth]

Great video, glad to have found this channel & yes next video on Sheekey's theory of aging please 😬🤗

[JM-usfr]

The hallmarks have definitely helped me understand this stuff much better, but I’m just a mathematician and have no background in biology. None of that compares to how much better of a perspective I get when I watch your videos though!

[lennihe]

Wow, that's the third video released in one week! Just catching up here.
I like the hallmarks of aging. For me, and I suspect a lot of other laymen, it broke through the misconception of aging as a linear process we are all going through at a more or less genetically predetermined rate. What's more exciting is the idea that we might be able to do something about it.
That the hallmarks may not be accurate does not concern me that much. After all, isn't science the pursuit of being less wrong? One step at a time, then. Perfection remains forever beyond the horizon.

[paulkabrna]

Paradigms are a solid foundation throughout the sciences. Where would we be without them. Mine is the Plate Tectonic paradigm :)

[ericrandolph]

Great presentation. López-Otín et al 2023 expands on the hallmarks of aging. I need to reread the original but I never considered the hallmarks a paradigm, more of a consensus. Like you said, a starting off point. Great job and great channel.

[Patrick-buvy]

Great work as always. I would be interested in seeing a video on why you think circadian rhythm disruption should be considered a hallmark of ageing. Keep up the good work.

[Celtokee]

Thank you, Sheekey, for aptly distinguishing the hallmarks of cancer from hallmarks of aging. Ms. Henrietta Lacks, the largest organism on planet Earth, would heartily agree with said distinction. Only thing missing in your brief but excellent overview--i.e., missing from the otherwise competent paradigms of de Gray and Sinclair—is that aging is fundamentally neither aberration nor an accumulation of errors, albeit accumulated errors is certainly a factor. By contrast, evolution from its very beginning was never about extending lifespan of individuals but rather upon maximizing biotic potential of a species. That is, to get as many of a particular species as possible to reproductive age. Period. End of story. That is “evolution” in a nutshell. Many cellular processes we are born with are evolved to help get us to reproductive age, after which age many of those same processes work against us, i.e., they cause what we term “aging.”

Btw, with respect to evolution, regarding the theories of the honorable Gregor Mendel and Charles Darwin, it happens that I’ve staunchly argued since high school (in the 1960s) that canonical Mendelian and Darwinian mechanics cannot possibly explain evolution, cannot explain the explosion of biotic diversity, cannot explain the rapidity of adaptation to environmental change evidenced by the evolutionary record. That entire, tiresome meme of “adaptation to random errors in DNA” e.g. supposed random DNA errors caused by cosmic rays--never washed with me. I did the math. If evolution were a “response to random errors, ” it would have taken not billions, not quadrillions, but rather quintillions of years. I’ve always argued that direct mechanisms of feedback from the environment to the genome must exist. Yes, I’m sorry, but I’m talking about long-pilloried Lamarkian mechanisms. Then, the explosion of understanding of epigenetics in the 1990s at long-last provided the missing evidence. For example, it has been demonstrated that repeated methylation of a gene causes a sequence change in that gene. I argue that that is a patently Lamarkian mechanism. Even if no one else does.

Re: p53, you might find of passing interest my 2014 article, “Multiple Cytoproliferative Effects of Elevated Pyrimidines are DNA-Synthesis-Independent, and Include p53 Repression.”

[gkile]

I appreciate your clear discussion of scientific paradigms, the distinction between hallmarks of cancer and hallmarks of aging makes sence but needs more exploration.

[titititi]

After doing my personal reasearch on aging and trying many supplements that purported to halt and slow aging, I come to realize that most of them if not all are useless to say the least. It's probably because the aging field is in its infancy. Or maybe we will never get to know the real cause of aging as human organism is so complex and enigmatic. I find following the aging field is so frustrating as sometimes it's hard to differentiate between real scientists and fad scientists. Or even worse, sometimes those reputable scientists themselves get involved with brands of supplements in the shape of advisor or board member. I think all these things doesn't bode well with believability of aging field. Plus, the claims those supplement companies do is utter nonsence, clear lies as none of it came close to the expectation at least in my case.

[BrentsTreehouse]

Evolution does not create topologies. Human minds do. Natural emergence has complex interrelationships that surpasses our topological and paradigmatic thinking. AI may help us make sense.

[AyubKhan-elkk]

A timely reminder that we need a paradigm shift!
The work over the past 30 years has been focused on the justification of individual markers and then attempting to cobble them together.... Not very smart!
Humans are a complex organism, we follow a development pathway from birth and progress through distinct phases such as puberty etc... We have master regulators within systems such as the sympathetic, parasympathetic and endocrine systems which manage two way communications...
Our longevity framework should primarily focus on strategies that extend the early adulthood phases and as secondary strategy use rejuvenation where early phases are past. For example strategies to minimise thymus gland entropy could have significant downstream impacts on organ vitality and is much more plausible than thymus regeneration at age 50 or 60.
In a nutshell maintenance has a higher multiple than repair!

Keep up the good work..

[bennguyen]

Regarding David Gems "The Hoverfly and the Wasp: A Critique of the Hallmarks of Aging as a Paradigm", and the more recent paper "The long lives of primates and the ‘invariant rate of ageing’ hypothesis" on

I understand that aging involves hundreds of genes that get expressed differently throughout your life... however, repairing the normal cellular damage caused by living doesn't seem to rely on knowing exactly how the damage was caused.

So would love to hear a friendly discussion on damage-repair vs epigenetics/methylation between Michael Rose (Hamilton Theory), Steven Austad, Joanna Mase, and Aubrey de Grey, David Sinclair, Nir Barzilai.. to determine what cellular damage is not in theory repairable. For example, Joanna suggests cells can either cooperate (which includes going silent/scenescent), or they become cancerous... if you try to undo scenescence, cancer will emerge!

[markveen]

My favorite hallmark of aging is "Luck". Dont think most people realise how many lotteries you need to win to be a supercentenarian. Even with the best genes. You would still be extremely fragile. Any fall, bacteria or virus could be the end long before you reach that point. And you probably dodged many bullets cell wise.

[livics]

Anyway, I think we age because life is based on Carbon, which is stable in binding with other molecules, but also pretty unstable.
Maybe we just need Silicium mixed with Carbon to be more resilient...

What about Thymus gland prevention of atrophy and what about Epitalon?

What about diet? Which one is best for healthy longer life?
Plant based with whole grains and legumes, or keto?
Plus I.F.
Plus what do you think of the Blue Zones?
What about supplements or lifestyle for healthy prolonged lifespan?

[Earwaxfire]

What about protein glycosylations (advanced glycosylation end AGE products, and fetuin glycosylations)? Also what is the simplest way to monitor aging?

[jgarma]

Eleanor, it would be useful to ascertain one primal cause of aging, which inevitably would have several downstream pathologically identifiable effects, but we’re not there yet. I agree with you that paradigms like the 9 “hallmarks” and de Grey’s 7 are useful, they don’t sufficiently tie things together, not only (in the hallmark’s case) the antagonistic/secondary and integrative/tertiary effects, but as you point out, the role of the microbiome and
Seems to me, from the perspective of aging interventions currently available to the public, we need to focus on nutrient cellular signaling; specifically, mTOR, AMPK and sirtuin pathways, as well as senescent cells. As you know, there are compounds that may be helpful with each of these.

[unholyquail]

Right now I am keeping to the Information theory of aging as main explanation, it explains the hallmarks but more and gives a better paradigm because it also shows how we should interpretate findings and explain them.