Hacker News Reader

Comment by axg11 | Hacker News Reader

I used to work in genomics. I think the quest to have a universal epigenetic measure of ageing will end up in a dead end.

Ageing is relative to a starting point and the variability between people in terms of phenotype is huge.

By way of analogy, would it be possible to come up with a universal measure of ageing for cars? Cars are a complex system made of thousands of components, each of which can age differently over time. Each car make and model will age in a different way. Some of the components even slightly improve in performance over time as they “break in”.

The best way to measure epigenetic ageing is relative to a starting point. There are few studies that follow the same people over time (longitudinal) because it’s difficult and expensive to pull off. We’ll eventually get there though.

View on HN

Counterpoints:

- The accuracy of current epigenetic clocks suggests it might not be a dead-end with average error of 2-3 years, across multiple tissues (and even Chimpanzees).

- The variability of an aging phenotype is not that high. We all loose bone density, loose teeth, hair turns white, memory degrades, wrinkles appear, etc. In other words - aging follows a pattern.

- The car analogy assumes that aging is caused by damage over time. But there is an alternative explanation: aging provides and evolutionary advantage for a species and hence is predetermined.

> The variability of an aging phenotype is not that high. We all loose bone density, loose teeth, hair turns white, memory degrades, wrinkles appear, etc.

People age at different rates depending on a wide variety of factors.

Progeria, over consumption of alcohol, too much stress, too much radiation from sunlight, etc.

The things you point to are measures of a biological age, not a wall clock age. While they do correlate, they're not 1:1. Some people age faster.

> But there is an alternative explanation: aging provides and evolutionary advantage for a species and hence is predetermined.

I don't buy this. We don't have a pre-programmed death. It's rather that we haven't had any genetic pressure to live beyond our current lifespan as it doesn't increase our offspring's chances of success.

There's little pressure from competing with children for resources. Look at how many people there are in the world today - the world supports billions of humans. There are far greater pressures being exerted in other ways.

I think we do have a pre-programmed death. Almost all creatures die when they get older so in order to look for evolutionary pressures we have to look across a long time period and far back. For one - if organisms wouldn't die evolution would not happen. Or at least the non-dying ones would stay behind and be left living in environments they are no longer suited for. For ancient creatures food and resources might have been scarce and so it was advantageous for non-evolving old members to die-off sooner.

Also, whatever we think about these epigenetic clocks, there are few things to come to terms with: 1) they work across pretty much all individuals (and people with progeria do exhibit older epigenetic age [1]) 2) they work across pretty much all tissues. I don't see how this could be explained through "damage over time". The way I see it damage should be random and not lead to something so predictable that we could use it to guess a persons chronological age with 2.5 year accuracy.

[1]: https://pubmed.ncbi.nlm.nih.gov/30048243/

I do too.

Look at the tortoise. We know some that have lived two centuries. They have their niche, do what they do, and live a very long time.

During their evolutionary journey to their current local maxima, I wonder whether they lived shorter lives?

> if organisms wouldn't die evolution would not happen.

Huh? The only requirement of evolution is that organisms sometimes reproduce.

So this is my view.

The immortal organism would not evolve. Imagine you and I lived 100K years from now. Other humans would evolve somewhat during that time but we would be fixed. Climate change might happen, new humans would adapt to the changing environment via evolution, but we would be stuck suffering the new environment.

The humanity example takes a long time to be noticeable. But for early multi-cellular organisms this would kick in much faster. Thing about micro organism fighting against toxins. The ones that do not evolve and adapt would die off sooner. And while they are still alive they are competing for resources with the newer versions of themselves. So for the colony it is advantageous for the older ones to die quicker since we already know they will be unnecessary sooner or later.

Now we evolved from these primitive creatures. And the mechanisms for things like aging, circadian rhythm, sexual reproduction, etc - we inherited from the early creatures. So regardless if the advantage of dying sooner is beneficial or not to the humanity now - the mechanism itself is far more ancient than humanity or even mammals.

From an evolutionary perspective, I think we can at least say that absence of death doesn't confer a selective advantage, else it would have appeared and radiated in several billion years of biological evolution.

It might even be that death provides selective advantage(s), which would account for its being a nearly universal feature of known life. A "pre-programmed death" mechanism would be consistent with this.

> A "pre-programmed death" mechanism would be consistent with this.

We haven't found this mechanism in humans. Cancer and heart disease simply don't impact child rearing.

It requires a great deal of optimization to rejuvenate cells after injury and simultaneously tamp down on uncontrolled proliferation (cancer). It's an extremely complex system. The evolutionary gradient to optimize this is probably steep, and we haven't climbed it since our form is more than good enough. (There are billions of us.)

People cite tortoises, but these animals have a slow metabolism. They don't eat a wide variety of things. They don't have many enemies. They're not burning very fast.

We're not comparable.

>Cancer and heart disease simply don't impact child rearing.

I'm not sure of that. There's data-supported discussion of possible contribution to offspring survival by grandparents [1]. If true, that would disclose a fitness benefit of familial long lifespan.

[1] https://www.smithsonianmag.com/science-nature/how-much-did-g... [not a peer-reviewed primary source, but a reasonable commentary on the matter.

Yes, but "in the wild", length of a human generation was much shorter than today. It still is in some developing countries.

People would start reproducing around 17, so around 40-45, you already would be a grandparent with multiple grandkids. This is still early for cancer or heart disease, unless you inherited some unlucky genes.

aging mostly happens after an organism reproduces, so there is no evolutionary pressure to maintain fitness. there is no pressure to develop maintenance mechanisms...

There would be plenty of pressure to keep reproducing indefinitely, just that then there might be too much competition between ancestors and descendants for the same resources.

> just that then there might be too much competition between ancestors and descendants for the same resources.

Why is that supposed to be a problem? Plenty of species will happily eat their own young.

Because changing conditions could necessitate the species adjusting to the new conditions as they change, if the young have to outcompete both the old and the new landscape there's a higher chance of an extinction event.

This reasoning has been invalidated by the proof that living ancestors can contribute to successful procreation and rearing.

Sugar is great because it quickly converts to energy, but its benefit doesn’t always increase with the amount consumed.

Only if aging is separate from growing. I'd be somewhat shocked if there is absolutely no relation between them.

Note: This is completely outside my expertise, so make of that what you will.

Couldn't an organism that ages more slowly keep reproducing longer?

My noob perspective is that generation periods are optimized for environmental change sensitivity.

Humans seem to reliably be able to handle environmental changes expected in their life spans. Other species not, and I dare say most other fauna has much a faster generation iteration rate because they are much more sensitive to the environment. Ergo evolution made their lifespans shorter so they can iterate faster and respond with a tighter gene fit to the environment.

Humans have their fitness less correlated by genes so a longer life span is allowed, but not boundless. In a sense every body must die so that new solutions/iterations can be ran.

Epigenetic clocks have been built for many mammal species, not just chimpanzees, and they seem to work reasonably well for them. But for chimpanzees some human clocks can be used directly, without adjustments - indicating how close relatives we in fact are.

What you're missing about the epigenetic theory of aging is that aging, in the epigenetic theory, is a programmed stage of life like puberty. The body somehow knows that it's time to develop secondary sexual characteristics and change growth patterns when a human reaches a certain age. The same machinery decides that the slow deterioration of the person should begin. If one could control that machinery, one could turn off that mechanism of aging. The disease progeria is a possible example of the epigenetic clock malfunctioning and running too fast.

The source of all this is perhaps the suprachiasmatic nucleus which is important to perceiving the passing of time and emits growth hormone releasing hormone which signals the pituitary to make growth hormone.

> The disease progreia is a possible example of the epigenetic clock malfunctioning and running too fast.

It's a great example, but if anyone wanted to know more, it's spelled progeria.

What are your views on the trial that reversed epigenetic age in optic nerves, allowing them to regenerate? https://www.nature.com/articles/s41586-020-2975-4

I think epigenetic age _does_ make sense for very specific systems. For example, just focused on the optic nerve. Good luck getting an optic nerve sample in a live human though!

I believe human trials are due to start on this soon if they didn't already. I will try to find the papers. In the mean time here [1] are the human cells.

[1] - https://www.sciencedirect.com/science/article/pii/S221112471...

A thirteen year old having low bone density, heart problems and degenerating joints would be strange, but for someone > 70 it’s almost expected. The car example is dumb because cars don’t have a built in mechanism for regeneration that is failing. Our bodies mechanisms for self-regeneration weaken and then we see all the symptoms of aging.

You made good points, but maybe you could have done so without calling the parent's analogy "dumb"?

The reason for pursuing clocks is to use them to assess the efficacy of longevity interventions. Currently, with an error bar ~3 years they are not bad at all, and can be used to assess aging relative to a starting point, as you suggest.

would it be possible to come up with a universal measure of ageing for cars?

Not universal or at least not easily or affordably. I can test each critical component and get a pretty good idea how much stress that component has been exposed to. Maybe the same could be done with mammals and we just test the critical components to get some numbers then apply a rough estimate of a score. Then perhaps a formula can be applied to the set of scores from all the critical components to assign a health score. I am considering the concept perfect is the enemy of good in this case.

Any thoughts on the organ-based biological age score that Bryan Johnson presents? More equivalent to monitoring all the components of the car.

I think these biological age scores are a really healthy way to debate and create broader awareness about a) how our bodies work and b) how we understand aging.

https://blueprint.bryanjohnson.co/

Organ-specific is the most promising in my opinion. It’s also more likely to be actionable. Different organs will “peak” at different ages.

Sounds like a task for data science.

Reply on news.ycombinator.com