47 replies to this topic

[jaydfox]

If evolution has not done it up until now, there must be a reason behind it, a reason so important that it prevents lifespans from exceeding a certain duration.

I doubt it. It took only a few million years for us to double our lifespans relative to chimps, and that was with several close calls with extinction applying selection pressures for just about everything except low intrinsic mortality.

Lack of adequate selective pressure for—and/or presense of a strong selective pressure against—longevity seems to be the problem. Evolvability, if tied to somatic mutation rates, would be a simple reason why we don't live longer. Dozens of other ideas come to mind.

Evolution may be bound by the pressures involved, to not have evolved beyond a certain degree of longevity. But that's no reason to assume that simple tweaks can't get us further. They might expose us to more extrinsic mortality risks in a "natural" environment, but we're long past that stage now.

One example is inflammation, which may serve a purpose in preventing/fighting infections, etc., a problem which we face much more rarely today than in millenia past. Reduced inflammation can allow increased longevity, via reduced crosslinking, etc. I suspect that dozens of such selection pressures and tradeoffs have been tilting in favor of longevity with each successive generation, for the last couple centuries or more.

I doubt it's so much a case of people with extreme longevity genes having a breeding advantage, as much as it's simply a lack of weeding out people who might otherwise have high longevity but would be killed before reaching reproductive age, or before they can raise their families. So I doubt humanity's new lifestyle is selecting for longevity, it's just not selecting against it as much anymore.

By not selecting for longevity, what I'm getting at is, what advantage to one's offspring would be provided by living to 100 or 110, when reproductive capacity ended 40-60 years before? Does my grandmother still affect my success, or my children's success? And she's only in her early 70's. What affect on one's great great grandchildren can one provide that would be a strong selection pressure? On the other hand, if such people face higher mortality rates before age 20, even if only 1% higher, that would be more than adequate to weed such genes out of the gene pool. Remove those pressures (which we probably have in some cases), and longevity will increase. Slowly perhaps, but it will happen, and faster than the millions of years it took to double our lifespans from that of chimps.

But, how do we do it in one generation? Biotech. Nanotech if necessary. Hmm, I'm getting a bit off-topic.

The point is, I doubt repair rates are enough, even at age 10, to sustain us much past 100 years. We need to do even better than that!

And more importantly, the point is, I don't think aging is just loss of repair capacity. The repair capacity was never there to begin with! Damage accumulates. That's aging. Loss of repair capacity accelerates the process, but even with non-diminishing repair capacity, we'd still age, and develop pathologies. We'd look young, but die of cancer, or heart disease, just as children do today, but at the rates of the elderly.

Sure, we might get a couple more decades, maybe three or four or five if we're lucky. But we need to improve the repair rates even more to live longer. That, and/or clean up accumulating damage. But since that seems a bit ambitious for an entire population of hundreds of millions or billions, improving repair rates seems as important as cleaning up the accumulating damage, at least in the short run.

[caliban]

META:

Alas, the power of technology has abandoned us: Apparently, I cannot move the entire discussion (since BJ's suggestion) to elsewhere without crashing the forum. Thus, the CIRA element is formally withdrawn. My sincere apologies to those who suffered from its application earlier on in the topic.

In response to Jay's first (fatal) comment, I personally would side with prometheus: The focus on repair is not invalidated by your "belief", it is a definitional requirement. If that entails that -on a genetic level- "aging" begins after fertilisation, maybe one has to bite the bullet after all. [huh]

[Mark Hamalainen]

Just because you haven't does not mean it does not exist. Anyway, I did say theoretically. The point is that even without division a cell could balance DNA damage via repair mechanisms and deleterious material accumulation via autophagy and exocytosis.

Please, explain how it could exist, theoretically. That it couldn't exist, even theoretically, was the most important point of my paper.

Mutations are probably one of the main causes of aging rather than "a part of aging". They can be prevented/reduced. But how can you say that immortal cells are "clearly aging" when clearly they do not become senescent or apoptose like normal cells?

I don't see how they can be prevented. Their rate can be slowed, but not prevented. Hence, they are clearly aging at some rate. Without replication and subsequent selection, or replacement of DNA information from another refernce, their probability of surviving will continually decrease with time.

Increase DNA repair and you prevent DNA damage accumulation.

No, you slow it.

Ensure that lysosomal function is maintained and deleterious materials are degraded. Those that cannot be degraded can be ejected from the cell by exocytosis.

This doesn't sound like a simple matter fixing of gene expression.

Each and every age-related intracellular physiological phenomenon that becomes discovered has a solution (at least in a theoretical sense until experimentally proven).

Sure, reproduce and let the somatic shell die.

What about ribosomal DNA?

What is your point?

You keep insisting that 'the cell' can repair any and all damages, but chooses not to. However, you have not provided evidence for this, nor a theoretical rational. That the germ line does not age and therefore we have the inherent potential not to is a fallacy. The germ line avoids MEPs by replication resulting in dilution, and by reproduction coupled with natural selection, which does not prevent change, so evolution is a controlled aging of DNA in one sense. I've already explained why natural selection won't save the somatic body.

These debates don't seem to be going anywhere. Slowing DNA mutation rates by definition slows a part of aging, but also by definition it cannot be a complete cure.

[DJS]

Jay

I'm saying that cancer incidence rates would hardly be affected if we maintained our youthful repair mechanisms. It's reliability theory.

I'm not so sure about this Jay. I agree that a robust and *youthful* rate of repair would not eliminate cancer - because even in a multiply redundant system an eventual breach of all fail safes is simply a matter of probability. However, to claim that cancer rates would "hardly" be affected by the continuation of youthful repair (or the upregulation of later life repair) just doesn't jive with me. The example that Prometheus often uses of XP shows that individuals with decreased or deficient repair have higher cancer rates across the boards. The path to cancer starts in so many different ways, whether it is protogenes being mutated into oncogenes, mutated cell cycle check points, the corruption of signaling transduction pathways...basically, I think of it this way: if cancer has to jump over a 100 ft wall to reach what we would consider to be clinical pathology, it may, if it made a hundred zillion attempts, jump the wall one time. However, if we lowered the wall to 10 ft, then the probablity of a successful jump would sky rocket.

[DJS]

Mark

There is no reason to suspect that we have evolved the ability to repair all of it (since much of it is on pathalogical only at ages which our species did not live to until recently).

This is a key point and one that makes a lot of sense to me. If damage is accumulating below a level at which fitness is affected, why would it be selected against? [huh]

[wraith]

Here's my current favorite definition of aging ( and theory of aging):



Gerontology 2004:50(5):265-290
Richard L. Bowen, Craig S. Atwood
Living and Dying for Sex. A Theory of Aging Based on the Modulation of Cell Cycle Signaling By Reproductive Hormones



Abstract

A mechanistic understanding of aging has yet to be described; this paper puts forth a new theory that has the potential to explain aging in all sexually reproductive life forms. The theory also puts forth a new definition of aging - any change in an organism over time. This definition includes not only the changes associated with the loss of function (i.e. senescence, the commonly accepted definition of aging), but also the changes associated with the gain of function (growth and development). Using this definition, the rate of aging would be synonymous with the rate of change. The rate of change/aging is most rapid during the fetal period when organisms develop from a single cell at conception to a multicellular organism at birth. Therefore, 'fetal aging' would be determined by factors regulating the rate of mitogenesis, differentiation, and cell death. We suggest that these factors also are responsible for regulating aging throughout life. Thus, whatever controls mitogenesis, differentiation and cell death must also control aging. Since life-extending modalities consistently affect reproduction, and reproductive hormones are known to regulate mitogenesis and differentiation, we propose that aging is primarily regulated by the hormones that control reproduction (hence, the Reproductive-Cell Cycle Theory of Aging). In mammals, reproduction is controlled by the hypothalamic-pituitary-gonadal (HPG) axis hormones. Longevity inducing interventions, including caloric restriction, decrease fertility by suppressing HPG axis hormones and HPG hormones are known to affect signaling through the well-documented longevity regulating GH/IGF-1/PI3K/Akt/Forkhead pathway. This is exemplified by genetic alterations in Caenorhabditis elegans where homologues of the HPG axis pathways, as well as the daf-2 and daf-9 pathways, all converge on daf-16, the homologue of human Forkhead that functions in the regulation of cell cycle events. In summary, we propose that the hormones that regulate reproduction act in an antagonistic pleiotrophic manner to control aging via cell cycle signaling; promoting growth and development early in life in order to achieve reproduction, but later in life, in a futile attempt to maintain reproduction, become dysregulated and drive senescence.

[jaydfox]

There is no such thing as irreparable biological damage - cells can be regenerated and crosslinks can be digested. Just because these abilities are not innate in humans does not mean they cannot be engineered via genetic enhancement.

Right. But we were talking about what's innate. Regressing someone back to the repair capacity of a 10-year-old does no good (well, probably some good, but not much) if a 10-year-old didn't have the necessary repair capacity, which is what I'm trying to get across. Aging isn't just because our repair rates fall with time, it's because they were never good enough to begin with! Hence, damage accumulates, even in youth. Hence, aging is not *just* falling repair rates.

Falling repair rates may be a major part of aging, and in humans and other very long-lived organisms, it may be the primary aspect of aging, but it is not the only aspect of aging. Damage accumulation must be considered as a part of aging until you can prove that it doesn't accumulate in youth. Good luck.

As Aubrey would say, there is something subtely different between a 20-year-old and a 30-year-old, even though on the surface they seem to have nearly the same state of health. That's why I love that sentence of his, because it makes clear that unseen damage seems to be accumulating.

[DJS]

Jay

As Aubrey would say, there is something subtely different between a 20-year-old and a 30-year-old, even though on the surface they seem to have nearly the same state of health. That's why I love that sentence of his, because it makes clear that unseen damage seems to be accumulating.

Its one thing to say there is subtle yet meaningful difference in the accumulation of damage between a 20 year old and a 30 year old, but what about the difference between a 10 year old and a 20 year old...what about the difference between a fetus and a 10 year old...a fetus and a zygote?

The question for me is when does damage begin? If we subscribe to Aubrey's model, would the organism need to be multi-cellular/ have an extensive metabolism for damage to accumulate? (In this instance I am specifically thinking about cross links and aggregates, not DNA damage) Would this preclude the stages of early development (morula, blastula, etc)? I mean, if we are operating under the assumption that some level of damage is getting by our maintenance and repair then there should be minute traces of it -- even in pre-adolecents. Has there been any evidence of this?

[DJS]

Prometheus

If by this you mean that humans, for example, did not live long enough to experience the deleterious effects of damage accumulation, there is no evidence to suggest such a thing. On the contrary, even if humans made it only to 30-35 years of age in pre-civilization times a 20 year old would still be fitter/more vigorous/more likely to procreate than a 30 year old.

Well first, I think that positing a 30 to 35 year average life span for our pleistocene ancestors is being overly generous IMO. Further, the current orthodoxy within aging theory (disposable soma/AP) would suggest that there is indeed a great deal of evidence that damage/aging usually did not have a chance to reach pathological levels in prehistoric times. In this regard you are not arguing with me, but Thomas Kirkwood (unless you interpret Kirkwood differently than I have, in which case I would love to be enlightened). Finally, I think that the last sentence of the above quotation is dubious. I am not at all certain that fitness, defined evolutionarily as the ability to pass on one's genes, is simply a matter of vigor -- especially in the case of a social primate species such as homo sapien sapien. One must also consider the heirarchical structuring (and consequently, issues of procreative seniority/mating rights) that may have accompanied early hunter/ gatherer groups and are independent of such issues as vigor. In my mind, the lowering of repair rates is directly relational to extrinsic mortality factors, which is once again a matter of probability; ie, a growing probability that an individual will get picked off by any number of extrinsic factors (disease, predation, etc) regardless of whether or not they maitain optimal fitness.

[jaydfox]

Its one thing to say there is subtle yet meaningful difference in the accumulation of damage between a 20 year old and a 30 year old, but what about the difference between a 10 year old and a 20 year old...what about the difference between a fetus and a 10 year old...a fetus and a zygote?

The question for me is when does damage begin? If we subscribe to Aubrey's model, would the organism need to be multi-cellular/ have an extensive metabolism for damage to accumulate? (In this instance I am specifically thinking about cross links and aggregates, not DNA damage) Would this preclude the stages of early development (morula, blastula, etc)? I mean, if we are operating under the assumption that some level of damage is getting by our maintenance and repair then there should be minute traces of it -- even in pre-adolecents. Has there been any evidence of this?

Well, from what I've gathered, especially in light of the recent announcement of "aging" in bacteria, I think the type of damage plays a big role. For nuDNA damage, I think it starts accumulating from conception. Statistically speaking, a zygote will probably not get any mutations. Any nuDNA does will, if not kept in check by the cell's becoming senescent or apoptosing (is that a word?), cause large portions of the fetus and eventual child to have that same mutation. If the mutation is serious enough, a miscarriage would ensue. For those that aren't serious, I think of them as "birthmarks", but instead of discoloration of large groups of cells, it's a pre-cancerous state where the cells are one or two steps closer to being dangerous than "normal" cells.

However, non-DNA damage will effectively be diluted by the rapid growth up to adulthood. So crosslinks, aggregates, etc., would not accumulate fast enough to be measurable. On the other hand, DNA damage should be. In fact, as part of reliability theory, there's mention of a high initial damage load. In my mind, this applies quite well to DNA damage, and quite poorly to non-DNA damage (unless larger systems than cells are affected as well).

A similar argument is had for mtDNA damage. A selection advantage to avoid autophagy doesn't apply particularly well to cells that are rapidly dividing (such as in zygotes, fetuses, children...), because there wouldn't be as much need for autophagy. So I would suspect that mtDNA damage would also accumulate from conception, but perhaps slower than in adulthood, due to the lack of selective advantage (which is due to "frequent" mitosis).

[Mark Hamalainen]

Something is directing this methylation, suggestive of a developmental program. It's not all about damage accumulation and a Hayflickean molecular entropy - that's my point.

I'm not convinced that methylation must be programmed at all, but I don't discout it either. I remember reading a few years ago about non-specific methyl transferases found in mammals a few years ago... but perhaps their regulation was just not recognized or understood. Could you post pdfs of those references? I'd be interested in your opinions of what the purpose of these programs would be if they exist, and how they could be averted/reprogrammed.

On the contrary, even if humans made it only to 30-35 years of age in pre-civilization times a 20 year old would still be fitter/more vigorous/more likely to procreate than a 30 year old.

Don, I liked your idea that physical-age is not the only determiner of fitness. However you look at it though, selective pressure does decrease with time, so there must be a point where accumulation is low enough to have escaped it, no matter where you believe that point is.

Lysosomal function and exocytosis are genetically regulated, ergo it can be "fixed" by gene expression.

Perhaps, but again I don't think its safe to assume that these mechanisms are complete. Has anybody read Godel, Escher and Bach? There's a chapter where one character is tricked into buying a record player on the sellers claim that it is 'perfect', i.e. it can play any possible record with perfect fidelity. The problem is that for every record player there exists a record that when played, the sounds produced resonate with the record player and destroy it. Apparently this problem is analogous to Godel's Incompleteness theorm, although I don't have the mathematical background to explain it very well (I suggest you read the book if you're interested).

Actually if the rate of repair keeps up with, or is greater than the rate of damage, DNA damage should not occur.

As long as there is some probability of mistake in repair (if we are to assume the second law of thermodynamics holds), there must be some rate of mutations. Even if the rate is miniscule, there are a lot of cells in the body. I'm not argueing that improving the efficiency of repair can't help us, just that it can't be a permanent solution.

[ss3steve]

aging: a terminal illness