This was an excellent post and I’ve gone through it several times to let it all sink in. Thanks for your insight!
Sorry. Not mine. Forgot to put the quotes.
That was from Fedichev - the answer to one of the questions he was asked. I figure people skim, so I quoted what was most insightful to me.
Below is the Q and A posted above.
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Fedichev’s thinking is interesting but I’m not sure his rationale extends enough beyond metaphor to be helpful, at least the way I think about it. In places, the reasoning about what there is to mean by causally indicative criteria for ‘aging’ seems circular.
To me the dependent variables for which we want to discover independent variables that explain a great deal of the variance are healthspan, and the conditions and diseases that negate healthspan or kill us outright. A theory of aging that does not generate a family of such IVs which, when empirically manipulated, demonstrate effects on DVs of interest seems more like a notion than a true theory that meets specific standards of independence and testability (among others). I’m happy to be wrong and I may need to read again (or perhaps someone can explain to me) but, at this moment, I’m not seeing a coherent theory in this person’s explanations.
How exactly does one dilute entropy?
Although it appears lobsters, NMRs and bowhead whales have figured it out.
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As long as we are talking (in the latter part of this thread) mostly about Peter Fedichev’s and Gero’s work, I thought I’d add this recent comment from Peter on the previous thread about brain aging (post he did quite a while ago - see here: The Problem of Brain Aging, Peter Fedichev
As with many Russians, he seems to have a very pessimistic orientation…
Peter Fedichev
(https://twitter.com/fedichev)
Let me revisit this unsettling chart I shared a year ago. It’s certainly alarming to see how our cognitive abilities decline with age, especially as we’re living longer. Combine this with a falling birth rate, and what do you get? Just look at the chart and see what this trend might mean for the average IQ of our population. We’re not just undergoing a demographic shift; we might be heading towards a society with a lower average IQ. This is a radical departure from the bedrock of our social norms and structures.
Traditionally, age was synonymous with wisdom. Elders in ancient societies were revered, balancing the impulsiveness of the young. Our political systems have always favored the older, supposedly wiser, generation for leadership roles.
But now, as life expectancy increases, we’re placing individuals in their 80s at the helm, expecting them to manage fast-paced, complex changes. With diminished cognitive sharpness (an euphemism for having no brain left), how can they truly grasp and navigate these intricate dynamics?
Could this be the underlying reason why, in these advanced, most illustrious times, we resort in conspiracy theories, power struggles, and conflicts – proven heuristics, a fallback to primitive, instinct-driven responses working well for reptile brains? So, my friends, brace yourselves. It seems we’re on a train hurtling towards a wall, with no nobody in charge.
Source: https://x.com/fedichev/status/1742611487309381787?s=20
And, for those who want more “Fedichev”:
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He’s definitely frustrated. I feel he’s 100% right. We need not only young plasma, but young brains too.
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I agree with that… not so much with this “We’re not just undergoing a demographic shift; we might be heading towards a society with a lower average IQ.” (at least I hope we are not).
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I had the same question and asked a physicist friend and he forwarded this, noting that it was not really an especially useful construct. According to what I see here it is more definitional.
2308.05025.pdf (337.6 KB)
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It helps to distinguish intelligence (a broad term subsuming many facets of adaptation, which is the most universal definition of intelligence) from IQ, which is what a very small number of carefully designed, normed, and validated IQ tests measure. For some time, what is known as the Flynn Effect described a gradual increase in IQ. More recently, that trend reversed and is trending downward. My own view, for which I have no hard data, is that human intelligence, including the IQ proxy is still gradually increasing but that some means and other measures of central tendency may not be increasing at the moment due to many factors. I think 75 year longitudinal trend data by decile would be interesting. I don’t know if anyone has published that but decades ago, when I was closer to that issue, many such datasets existed that could produce such an analysis, even if the findings were not completely representative of the general population. Also relevant here, I don’t know if the IQ data generally reported to be declining co-mingles scores from young children, older children, and adults. The validity of an IQ test score drops rapidly with age. By the time you shift to adult tests of IQ, contamination with other factors is significant. A longitudinal analysis of young children and one of adults might tellus two different things.
Through single-cell DNAm (scDNAm) data from aging animals, we demonstrate that this signature captures the exponential expansion of the state space volume spanned by individual cells within an aging organism, and thus quantifying linearly increasing configuration entropy, likely an irreversible process. Consistent with this interpretation, we found that neither caloric restriction (CR) nor parabiosis significantly impacts the entropic feature, reinforcing its link to irreversible damage.
…Irreversible in principle, or just for most of human history? Development robustly selects the correct initial volume in state space, and I think it’s a matter of finding what are the relevant cell type-specific signals it uses and being able to selectively induce them. Obviously doing this across an organism is an enormously difficult engineering problem in practice, but reprogramming approaches have already made some promising strides.
Looking at the practicalities I think Mitochondrial DNA mutation caused by oxidative stress is in itself entropic damage. Although directly it cannot practically be repaired we can sweep away the damaged mitochondria in which the mutated DNA causes problems and fix the problem at a larger scale by growing new healthier mitochondria.
Mitochondrial inefficiency is part of the issue. Senescent cells is another part of this issue both of which combine to reduce cytosolic acetyl-CoA levels. The level of acetyl-CoA can be varied by exogneous citrate and acetate (I think citrate is more effective, but you can use both at the same time).
Here’s a fairly new (12/2023) article on the latest 3rd generation Epigenetic Clocks - DunedinPACE and Peter Attia’s view.
" EXPERT DIALOGUES: Response to Dr. Peter Attia’s Weigh-in on Biological Age Clocks."
https://trudiagnostic.com/blogs/news-for-our-customers/industry-dialogues
"
Comparing even PhenoAge, we see that the hazard ratios are 1.57 for DunedinPACE and 1.14 for PhenoAge, while the DunedinPACE has a higher hazard ratio in every other comparison.Even with that said, we still have newer clocks. Most notably, SystemsAge which was developed by Yale and OMICm Age which was developed by Harvard and Trudiagnostic. Together, these new clocks offer even more features such as the ability to differentiate between heterogeneous types of aging and show even higher association to disease outcomes.The noise of biological age clocks, both biological and technical, are also topics which Dr. Attia brings into consideration. This is for good reason as both of these have been large limitations of the clocks. However, once again, new techniques and clocks have significantly improved from what Dr. Attia mentions in his post.In another paper, Dr. Horvath mentioned the following: “Another potential benefit of using DNAm-based biomarkers instead of plasma biomarkers is that the DNAm-based biomarkers are representing a longer average estimate of the biomarker concentration and are not as affected by day-to-day variations that could bias the results.”
Thus, if we are worried about transient variation of DNAm clocks giving us wrong information at the point of time, the incorporation of traditional plasma biomarkers through epigenetics might be able to improve this. It might even show that these biological locks can act like HbA1C or three-month running averages of current aging trajectories.
In fact, OMICm Age and GrimAge have both used this approach. They have incorporated DNAm predictors of other clinical variables to incorporate biological signals into these clocks. GrimAge did it initially with 8 plasma proteins, but recently incorporated DNAmHbA1C and DNAmCRP in GrimAge2. The outcome was that GrimAge2 has better hazard ratios to disease than the previous version.
Conclusions
Biological clocks do respond to interventions we know positively affect biological aging (caloric restriction). They are extremely precise with many newer clocks showing less than a 0.5% variation. They are starting to incorporate multiple features of biology in 2nd and 3rd generation clocks which are trained to predict metabolites, proteins, and clinical values. They are controlling for immune cell characteristics to improve cell type variation. Lastly, they do show the ability to predict death over chronological age and even blood based biomarker methods.
Here’s another thing. As I think about what a BioAge clock is telling you, I think that the accepted definition is that it tells you how much longer you are likely to live based on the averages of the markers it’s using - blood panel, epigenetic, etc. But I’m unclear on exactly where it gets those averages (global?). So, if global life expectancy for men is 70 (higher in developed countries) and I want to live to be 100, do I want my BioAge to be 30 years less than my ChronoAge? No, but it gets complicated. I’m 70, so what is the BioAge I’m looking for to give me an average chance to live to be 100? (obviously maintaining your health on an even keel). Another factor is life expectancy goes up the older you are. See here:
https://www.visualcapitalist.com/charted-american-life-expectancy-trends-2023/
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You dilute entropy by growing. Cell growth and cell divisions are usually necessary. As an analogy, imagine you build a brand new house and start living in it and imagine as soon as you start living in it you slowly accumulate trash in the house. Lets say you cannot move the trash out of the house, and once enough trash has accumulated in the house it becomes uninhabitable. How do you keep that from happening? Lets say you are able to make your house bigger and divide it into two houses, and you can keep making more houses. When you build a brand new house, it initially has no trash, so you can take some of the trash from your old house and put it in the new house. Now you have diluted the trash by distributing it between a larger space. If you keep doing this you can delay the point at which your houses get full of trash and make them liveable for longer.
In a similar way, cells can dilute a lot of damage when they grow and divide. That’s one of the main reasons cells like the HeLa cells can be immortalized in culture, because they never stop dividing. This is also a big reason why animal models that continue to grow are not good models for humans. You can’t say we should be able to live forever because HeLa cells can. Humans are not continuously growing double their size frequently like these cells are.
Btw, lobsters continue growing throughout life so that would be one of many reasons they live pretty long and seem to not age. But I think it’s wrong to assume they do not age.
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We also constantly grow: ears and noses become bigger 
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I’ve always heard that lobsters die of exhaustion. At one point, they are so large, that they can’t make a new larger shell and the effort trying to do so kills them.
Size is everything when it comes to a lobster’s longevity.
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Hahaha - it seems that way - DesertShores has said. But hear me out - read to the end.
But actually not. You may have heard that your nose and ears never stop growing. As you get older, you might notice that your nose looks bigger or your earlobes look longer than they did when you were younger. Is there any truth to the idea that they are still growing?
Your nose and ears indeed change as you get older, but it isn’t that they’re growing. Instead, what you’re seeing are the effects of skin changes and gravity. Other parts of your body change in the same ways, but your ears and nose are more more noticeable.
Noses and ears are made of cartilage, a flexible tissue that’s harder than skin but softer than bone. It wears down over time and doesn’t give as much support to the skin on top of it. Your skin also loses elasticity and firmness over time, and it tends to sag. Loose or sagging skin over a weaker cartilage frame makes ears and noses look longer.
I have actually noticed a reversed trend since taking rapamycin for 3.5 years. About 6 months ago I noticed my nose seeming to shrink (very firm and tight - making it seem to reduce in size - crazy!) - and sinuses feel more moist and full - blow my nose often to clear all the wetness - but not from illness. My ears also very tight when flicked with my fingers. Perhaps rapamycin is strengthening the cartilage in nose and ears. My facial features are smaller and tighter along with the plumping of my face - which as we age can get hollow looking from loss of fat. In addition to this - my seasonal allergies have also stopped. Going from moderate hayfever spring and fall to none past 3-years.
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I’m inclined to believe this. If your nose were getting longer, I would feel the opposite.
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How exactly does one dilute entropy?
You have to remember that entropy is a mathematical concept. The physical interpretation is already difficult when you talk about increases and decreases, so it’s not helpful to start using verbs like dilution To say that growing dilutes entropy is at best meaningless for many physical systems, and for many others (if you take dilution as synonymous with a decrease) it’s flat out wrong.