26 replies to this topic

[olaf.larsson]

What impact would an unified aging theory have on our research area?

[Lazarus Long]

If a true unified theory of aging could be developed it would point the way to integrate various approaches that could assess their relative importance along with predicative values for results. For example to address mitochondrial mutation vs. telomere shortening in terms of relative importance in relation to a larger picture.

This does not mean that either is unimportant only that the relational impact of two such distinctly separate mechanisms might be better understood along with tissue regeneration, immunity, development biology, and a dozen or so other genetic aspects like gene switches and CR etc.

Once such a panoply of contributory systems and subsystems can be understood under one complex but comprehensive theory then we could better foresee consequences in a predictive manner for altering one that might in turn influence another, either positively or negatively or we can also better understand how a little tweak in one area combined with a significant tweak in another could have a profoundly greater positive impact synergistically.

Or we can make a better determination of how to focus our efforts for maximum effect and/or which approaches might work but yield little significant return of effort.

That is just my opinion but does it make sense to you?

Look at the situation with antioxidants for example; the logic of their use is sound but the results do not warrant the effort made, in fact some studies have now alluded to negative impacts from certain combinations of them. A true unified theory of aging should adequately explain these conflicting results, and perhaps shed light on how to properly use them to maximum effect; especially in conjunction with other integrated approaches.

[kent23]

Would high-throughput metazoan gerontology help? A unified theory of aging might be got at through a transmetazoan approach informed by evolutionary relationships. High-throughput metazoan gerontology could potentially be enabled by lab automation. A unified industrial process amenable to experimental variation and fine-tuned manipulation could allow researchers to interrogate extremely complex systems with data acquisition speeds orders of magnitude greater than that currently considered state-of-the-art. Age-related phenomena such as oxidation, matrix stiffness, and toxic aggregate accumulation could then be studied with huge rigor and precision in vivo. Perhaps an early unified theory of aging will = a predictive simulation in silico. At some point perhaps an AGI will be the only remaining sentient thing able to marshal the data and plan experiments.

How to support a unified theory of aging? Show that it enables long-term organism-level outcome prediction by a biomedical AGI.

If we had a U.T.A., would we need a U.T.A.? It might just be for fun at that point, not for the humanitarian purpose of curing aging.

I propose that possibly we cannot have it without the will to collect truly enormous loads of data. The system that I manipulate in the lab (Drosophila genetics) seems like an Amazon rain forest of wild mechanistic diversity, and yet we've barely seen the canopy. I have been daydreaming a little lately about what would be the implications if I could manipulate and transform millions of mutants in a miniaturized assembly line. I don't know how many Drosophilists are quite that nuts; for me it's an undergraduate apprenticeship in lab work.

How much do we need to understand in order predictably to rejuvenate an aged human being? Will a unified theory of aging be necessary? I can see it going either way, but not early on. For now let's repair as much damage as we possibly can. If that doesn't work, interface with... systems gerontology? Either way, you don't need a theory of thunderstorms to keep your roof from leaking.

Edited by kent23, 20 December 2006 - 01:44 AM.

[kent23]

Aww, man, I ain't got no beef with the downstairs kitchen, which far as I know it has never been splashed by leaking rain. There are also the architectural blueprints for the house, with which I could, potentially, build another. Heck, my house can even cause other houses to be built just by slamming my driveway into other houses' garages.

Of course, I could not run such an estate without both carpenters and cooks... I also need a chauffeur and a gardener. Some of these are better hires than others. Like Throckmorton, he’s a bit sketchy. Delicious pancakes, though.

But in the long run if the roof leaks and the place looks like a sty, my loyal servants will flee their guest quarters and look for other employment in, say, street performing or petty larceny.

Sometimes I wonder, though, if the downstairs kitchen were transplanted to the third floor, next to the library, say, how long would the roof hold out? I also worry about the chef, Throckmorton, setting fire to the joint one day when he's been drinking too much and leaves a pot of lentils on a lit stove for six hours. This place is full of intrigue. It's a Victorian novel on DMT.

Interconnectedness and complexity, no doubt- and who says otherwise? I say hurrah to convincing “the body's stem cell niches that they are operating in a more youthful environment and consequently enable them to regeneratively support physiological function for longer periods.” I’m a big fan of Irina Conboy’s work, for instance. There’s no cognitive dissonance, to me, in deciding that I want to assist in testing the hypothesis that identification and removal of everything we can profile as “age-related damage” will ameliorate a large chunk of age-related illness. I see the kind of work you’re talking about as directly connected to the testing of this hypothesis. A great synthesis could emerge- a robust systems gerontology. Identifying, targeting, and removing damage will flow directly into the process of characterizing our perturbations, which will flow back into perfecting them. Everything anyone is doing to responsibly realize rejuvenation will feed into this synthesis, including your research and that of many others.

Your “immortality funnel” is another useful metaphor, like the house. This could be like the safe in the basement with my diamonds and the architectural plans. Actually, put whatever you want in the safe, it’s called a “safe” for a reason. The safe contains enough liquid assets to get a whole Monopoly board of houses built. It might even be home to a super-intelligent dwarf who could keep everything in the house perfectly in order forever, except that he won’t come out of the safe. I salute your efforts to get him out of the damn safe.

Edited by kent23, 20 December 2006 - 04:27 AM.

[bgwowk]

If we can understand the evolutionary "rationale" behind aging we can investigate how we can develop a molecular "rationale" inhibiting aging.

I thought this question was settled back in the mid 20th century. The remarkably tight correlation between rates aging and rates of death due to exogenous causes in nature suggests pretty conclusively that organisms age whenever there is no selective advantage in not aging. We age rapidly in our fourth, fifth, and sixth decades of life for the simple reason that almost all our ancestors were killed in their third decade of life by pathogens and wild animals. Interestingly, that means that the recent ascendancy of humans to the top of the food chain means that within a few millenia human lifespans would naturally evolve to be more like other animals with virtually no natural predators, like whales and sea turtles (centuries). But of course technology will kick in long before then.

None of this says anything about the *mechanism* of aging. But the realization that the same basic mechanism occurs 30 times faster in mice than men solely for the stupid reason that mice ancestors were preyed upon 30 times faster than human ancestors suggests that the mechanism is highly adjustable. It means that there is no deep metaphysical reason humans live three score and ten. It means that critics of interventive gerontology who insist that present lifespans are ideal are basing their standard upon the rates at which their ancestors were eaten by sabre tooth tigers. That's a stupid standard if there ever was one.

[jaydfox]

I thought this question was settled back in the mid 20th century. The remarkably tight correlation between rates aging and rates of death due to exogenous causes in nature suggests pretty conclusively that organisms age whenever there is no selective advantage in not aging.

I'm not an expert on this, but it was my understanding that there are similarly tight (inverse) correlations between specific metabolic rate and aging rates. Statistical outliers do show a correlation with reductions in extrinsic mortality rates, but they also show specific changes in e.g. mitochondrial membrane composition that haven't been selected for in similarly long-lived organisms with lower SMR's. For me, it's quite undecided exactly what role extrinsic mortality factors play in relation to intrinsic factors such as specific metabolic rate. Aging is extraordinarily complex, and I think it's a gross oversimplification to say simply that aging was selected for, or rather that a non-aging phenotype was not selected for. Obviously evolution has had a hand in determining lifespans, but the why is, for me, quite a bit more complex than simply "because living longer wasn't enough of an advantage". That statement doesn't help us understand how we can tweak the existing machinery, so it's really a cop-out, IMO.

BTW, I'm not aiming this at you specifically Brian. Neither one of us is the expert in this arena.

[maestro949]

Will a unified theory of aging be necessary?

In my opinion yes. And I believe we already have the basis of a unified model in the Reliability Theory of Aging. The RTOA computes on all levels of biology, is comaptible with evolution and provides a core framework for which all other aging observations fit. All life is a state machine built upon redundant and overlapping autocatalytic chemical reactions that function within a network of higher level systems. We need look no further than RTOA for a theory. We need to simply flush out the details to see where we can prop up the various interacting network of biological systems whether it be gene expression, preventing and fixing damage, tuning the immune system, etc.

[jaydfox]

I agree that the RToA is a great start. The details are critical, however, as it's likely not anywhere near as simple as the basic models often used in explaining reliability theory. For example, there are scores if not hundreds of genes, mutations of which can promote or inhibit cancer. It's not as simple as a system with 4-6 redundant components, or even 20-25. There are hundreds, and many of the components are themselves systems to which we can apply reliability theory. And not all of the hundred need fail, but there are probably hundreds if not thousands of subsets that comprise a "failure mode" of the overall system.

The idea of a constant failure rate for given components is also unrealistic, since things like genetic mutation rates are likely to increase once genetic regulation becomes impaired, and genetic regulation is only one system in the greater whole, on a cell-by-cell basis. The failure rates of many components will be interconnected.

So while reliability theory helps us with the math and with organizing the various factors, ultimately it's a simplification just like other theories. A UTA would almost surely include elements of relaibility theory, but the overall theory would be more complex.

Er, in my non-expert opinion...

[xanadu]

I don't think we will ever have a UTA simply because there are so many different causes of aging and so many factors that effect those causes. We may however be able to summarise the main causes and have fairly effective strategies to deal with them. Many things will be found to be interrelated. Sugar, for instance, will be found to be a major cause of aging. Not just the substance itself that we ingest but the way we metabolise it. AGEs are widely seen to be a major cause of aging and sugar cross linking is central to AGEs. Sugar may be at the top of the list followed by other closely related factors like excercise, caloric intake, diet, vitamins and supplements.

I think that we may have to fool around with cellular machinery to get the most lifespan out of our bodies. This 50 replication limit, or whatever it is, has to go. Tellomere shortening may be a major factor in that.

[bgwowk]

Prometheus wrote:

No doubt there is no metaphysical reason. But there could be a reason. Consider if some processes have evolved in such a way as to "take a ride" on the mechanisms behind aging. Oxidation reactions, for example, are metabolicaly indispensable and oxidation by-products are used as cues for many oxidation-coupled and oxidation-sensing mechanisms. Why not couple the rate of, say, DNA mutation with immunoglobulin recombination? Why not couple the rate of evolution with mutation, for that matter?

I meant that there is no reason, other than ancestral predation rates, for the *rate* at which we age. The reason for the existence of the mechanisms that underly aging is a separate issue. I see now that what you meant by evoluntionary "rationale" for aging is different than the issue I was addressing.

Jay wote:

I'm not an expert on this, but it was my understanding that there are similarly tight (inverse) correlations between specific metabolic rate and aging rates.

That's not the case. Compare birds to rodents of similar size and metabolic rate. Birds age slower. Birds of prey are particularly long-lived. Some of the best proofs of the relationship between predation and aging are intra-species variations. For example, there is an island-based community of raccoons believed to have become isolated from their mainland relatives about a millenia ago. With fewer predators, they've evolved to age markedly slower than their mainland relatives. I doubt they have signficantly different SMRs.

Small animals have high SMRs because they lose heat fast, and small animals tend to be prey. I think that's the extent of the connection between SMR and aging.

Aging is extraordinarily complex, and I think it's a gross oversimplification to say simply that aging was selected for, or rather that a non-aging phenotype was not selected for.

I'm not saying either. I'm just saying that selection favors animals that don't age up until the age when they are typically killed by exogenous causes.

Obviously evolution has had a hand in determining lifespans, but the why is, for me, quite a bit more complex than simply "because living longer wasn't enough of an advantage". That statement doesn't help us understand how we can tweak the existing machinery, so it's really a cop-out, IMO.

There are different kinds of "why". Consider all possible valid answers to, "Why does the sun shine?" "Why do we age" is like that. Of course for interventive purposes we want to know the physiological mechanisms in detail. But the question of how the mechanisms came to operate at the rate that they do in different species in interesting too, and not without practical implications. In particular, the facility with which predation rates drive aging rates in nature suggests that a limited number of genes are involved, and therefore that rates of aging might be controllable with relatively minor genetic changes.

Edited by bgwowk, 20 December 2006 - 07:41 PM.

[jaydfox]

Small animals have high SMRs because they lose heat fast, and small animals tend to be prey. I think that's the extent of the connection between SMR and aging.

Ah, but that's merely an opinion. There's a correlation, while we can dismiss it based on hunches, we need something more rigorous. Various theories, including de Grey's mitochondrial free radical theory (developed in late 1990's, possibly out of date based on current research), make the connection between SMR and aging rate much more explicit, not due to a coincidence that both correlate with size.

[jaydfox]

Consider all possible valid answers to, "Why does the sun shine?" "Why do we age" is like that.

A more interesting question is "When will the sun be extinguished?", and that relates to "When will an organism die of aging?". Or more interestingly, "Why will the sun be extinguished in that time frame?", versus "Why does an organism age at the rate it does?"

Looking primarily at the proton-proton cycle, one might overlook the effect of the CNO cycle. Of course, in our sun, the CNO cycle is relatively insignificant, yet in a start just a few tens percent larger, it's the dominating factor in fuel burn rate. And this is just the tip of the iceberg of that question. Finding a formula to determine the aging rate of a star (or an organism) based on size doesn't answer the question of why stars slightly larger than the sun have a very rapidly increasing fuel burn rate (I believe the CNO cycle scales at the 17th power of temperature). So there is a transition point in the size:lifespan curve of a star.

Anyway, getting off subject, it was just an analogy anyway...

[Karomesis]

For example, rather than seeking to alter the genome of all the cells in the body through brute force methods that rely on as yet to be discovered technologies, it would be much simpler and more efficacious to "convince" the body's stem cell niches that they are operating in a more youthful environment and consequently enable them to regeneratively support physiological function for longer periods

Harold, correct me if I'm wrong, but isn't that similar to what they're trying to do with stem cells at the moment?

how much of a "rejuvenation" like effect do you think it would have to convince the ASC that they're young again?

[bgwowk]

Wikipedia on the Evolutionary Theory of Aging:

The major testable prediction made by this model is that species which have high extrinsic mortality in nature will age more quickly and have shorter intrinsic lifespans. This is because there is too little time before death occurs by extrinsic causes for the effects of deleterious mutations to be expressed and, therefore, selected against. This is borne out among mammals, the most well studied in terms of life history. There is a correlation among mammals between body size and lifespan, such that larger species live longer than smaller species in controlled/optimum conditions, but there are notable exceptions. For instance, many bats and rodents are similarly sized, yet bats live much, much longer. For instance, the little brown bat, half the size of a mouse, can live 30 years in the wild. A mouse will live 2-3 years even with optimum conditions. The explanation is that bats have fewer predators, therefore low extrinsic mortality. Thus more individuals survive to later ages so the force of selection against late-acting deleterious mutations is stronger. Fewer late-acting deleterious mutations = slower aging = longer lifespan. Birds are also warm-blooded and similarly sized to many small mammals, yet live often 5-10 times as long. They clearly have fewer predation pressures compared with ground-dwelling mammals. And seabirds, which generally have the fewest predators of all birds, live longest.

Bats and mice are a great example. Another is the naked mole rat compared to other rodents:

The oldest rodents living in captivity are the naked mole-rats (Heterocephalus glaber), the oldest of which are now at least 26 years old. Because of their living conditions they are less at risk of being killed by predators or accidents in the wild than are other rodent species. Therefore their longer natural lifespans are predicted by the evolutionary theory of aging. There was no big selective pressure for them to be more vigorous when younger and instead the selective pressure on all the genes that affect aging was toward longer lasting compoents.

Amazingly, not only do these rats live ten times longer than other rodents of their size, they even have higher oxidative stress as a recent study showed:

The long-lived naked mole-rat shows much higher levels of oxidative stress and damage and less robust repair mechanisms than the short-lived mouse, findings that could change the oxidative stress theory of aging.

Whatever the underlying biochemical events that underly aging are, and how they came to be, extrinsic mortality (especially predation) is why species age at rates they do. Human lifespan is what it is for the stupid arbitrary reason of how fast our ancestors were eaten by wild animals. Even if nothing mechanistically useful ever comes out of that observation, it's a powerful point to raise against those who would argue that there is something special about present human lifespans that cannot or should not be changed.

[jaydfox]

Whatever the underlying biochemical events that underly aging are, and how they came to be, extrinsic mortality (especially predation) is why species age at rates they do.

1. It doesn't explain how to intervene in the aging process.
2. It doesn't explain why one anti-aging system would develop versus another: that would be explained by which had the least "cost" involved, and/or the greatest coincidental benefit, and hence could be tolerated despite only a weak selective pressure (or a weak decline in extrinsic mortality) for longer lifespan.

There are also other factors which would logically affect aging rates if they existed, such as mutations that increase the rate of aging but increase evolvability in a hostile, changing environment. The naive reliance on extrinsic mortality alone proves there is a connection, but it teaches us almost nothing of value about the rate of aging in species, and how to intervene. I'm not saying that extrinsic factors don't determine the rate of aging: I'm saying that how they determine the rate of aging is useless from a biomedical standpoint.

[bgwowk]

The appropriate response to Darwin's theory of evolution is not, "So what? It doesn't say anything about how to improve medicine." It's, "Hey, cool! So that's how we got here!"

The evolutionary theory of aging in its most general form-- that anti-aging changes are not selected for, and pro-aging changes are not selected against, after extrinsic mortality takes hold --is both trivially correct, and borne out by spectacular natural examples. That the theory doesn't in itself tell you how to intervene (except by removing predators and waiting a long time) does not subtract from the truth of it.

Perhaps you are objecting that I'm side-tracking the thread with a trivial truth not relevant to the goal of short-term intervention. But even that's not completely true. If affecting the rate of aging, as opposed to treating and reversing aging (SENS), is regarded as an intervention, then what we see of the evolutionary theory of aging at work in nature sets bounds on the number of genes involved, and the practicality of finding and modifying them.

[bgwowk]

I know its a tad tangential but I'm curious, Brian: what part of SENS in your opinion looks at reversing aging?

If you break crosslinks and cleanup intra and extracellular waste accumulations, then you are reversing aspects of aging. More generally, if you enumerate all delerious changes due to aging, and then fix them all in a manner that results in biological equivalence to a younger age, then you have effectively reversed aging. SENS, as currently formulated with WILT and all, doesn't do this. But literal reversal is the logical ultimate goal of an engineering approach to aging intervention. This is distinct from merely tweaking genes that affect rates of aging, and that was my point.

[maestro949]

Isn't that the tricky part - enumerating all the deleterious changes? One may look at wrinkles and say, that is a deleterious change: therefore let's treat wrinkles and we are treating aging.

Exactly. Some changes will be cause and some effect. Some both. This is why we need to flush out what triggers are at the top of the cascade. There may be only a handful of pathways we need to target, e.g. a breakdown in DNA repair mechanisms.

Edited by maestro949, 22 December 2006 - 10:39 AM.

[bgwowk]

My original point was that nature shows us that rates of aging can be affected dramatically by natural selection of genes. However there are no examples in nature of the *direction* of aging being reversed by evolution. So there is no reason believe that any simple genetic manipulation could comprehensively reverse aging.

SENS, as currently conceived, doesn't comprehensively reverse aging either. But if it is successful in intervening in the seven identified cellular effects of aging, and if these effects indeed cause most pathologies of aging on timescales less than a century, then the current conception of SENS will buy enough time to develop more comprehensive solutions *even for people who are already aged*. That is the rationale for SENS as I understand it.

Of course you want to go after the causes of aging at the earliest, most leveraged points. But you need treatments for aging that has already occurred too. And for that, there is unlikely to be any substitute for going in with enzymes and ultimately engineered organisms and devices and cleaning house.

[1966]

This idea should be checked by experiments.
Maybe "biological clock" is not located in the cells but in the cell's enviromnent, perhaps it the cellular matrix. "Aged" cellular matrix would send signals to surrounding cells to enter cellular senescence.
Appropriate signals from the environment should, then, be able to rejuvenate the cell (if it is capable of that).
The role of the cellular environment and cellular matrix in the aging of cells and multicellular organisms should be explored by experiments (as far as I know, as a rule, unicellular organisms do not age).
Survival of life from generation to generation points to cell signaling as involved in ageing of cells and multicellular organisms.