47 replies to this topic

[caliban]

Topic is moderated, (CIRA) all serious contributions welcome.


Question:

In a sentence, what is your favorite definition of aging?

[jaydfox]

In a sentence? Hmm, toughy. My favorite definition to date was that offered by Dr. Aubrey de Grey in a public debate I viewed at SAGE Crossroads.

The definition he offers is several paragraphs, so I'd like to pull out a couple short choice quotes.

So a thirty-year-old, for example, is more or less in as good condition in terms of how they work, as a twenty-year-old. But we know there is something subtly different about the thirty-year-old because the thirty-year-old has a shorter remaining life expectancy.

I love this point he makes, because it points out something spectacular. Aging is pretty obvious above age 60 or 70, where the degeneration of aging can be measured almost annually. But a 20-year-old and a 30-year-old can both be in near-perfect health, and yet there's something fundamental—at the cellular or molecular level, something invisible to us—that's different, that makes the 30-year-old have on average ten fewer years of life left than the 20-year-old. We can't see what that difference is, yet it's there. Such an appreciation is important to have.

Aging is a side effect of being alive in the first place.

If all you get is one sentence, that would be the one.

[kevin]

Aging is the entropic increase in the disorder of a biological system which negatively affects its capacity for self-renewal eventually leading to system collapse.

[Michael]

All:

Modified from Strehler and Hayflick's respective def'ns:

"Aging is the universal, progressive, and deleterious process of escalating loss of molecular fidelity with age, resulting stochastically from the intrinsic metabolic processes of the organism, that degrades its ability to maintain homeostasis in the face of environmental stressors, leading to increased vulnerability to pathology and mortality."

-Michael

[jaydfox]

Hmm, perhaps instead of a one-sentence limit, we just need a word limit. Michael Rae's clocked in at 47 words. Maybe a 50-word limit? Dave Gobel's partial to the 40 word limit, the supposed maximum attention span of pop culture magazine readers (such as Rolling Stone).

In fact, that had a lot of big words. Maybe just a character limit? With spaces, Michael Rae's clocked in at 345 (347 including the quotes).

I suggest a 150 and a 400 character limit, the former for a quick and dirty category, and the latter for a more descriptive but still succinct category.

[jaydfox]

Three words, 19 characters, bravo!

Of course, that's actually more of a property of aging than a definition, so I'm issuing a penalty.

[caliban]

Many thanks for your contributions so far.
I think what we have got is rather good certainly better than many of the popular definitions out there.

Taking stock:

1) (jaydox)

Aging is a side effect of being alive in the first place

Not very descriptive and arguably untrue.

2) (Kevin)

Aging is the entropic increase in the disorder of a biological system which negatively affects its capacity for self-renewal eventually leading to system collapse.

Thats a rather good one. Firstly, I'm not sure about the entropic part, but one could leave that out. Self-renewal: In what sense do "immortal" cells self-renew when they divide? The crucial point here is "disorder" and that is probably in need of definition.

3) Michael

"Aging is the universal, progressive, and deleterious process of escalating loss of molecular fidelity with age, resulting stochastically from the intrinsic metabolic processes of the organism, that degrades its ability to maintain homeostasis in the face of environmental stressors, leading to increased vulnerability to pathology and mortality."

I like the combination but it bears some of the sins of its parents. Universal does not help, even if meant to apply to only the individuum. Molecular fidelity? Thats contentious. How do you distinguish from other types of metabolic pathology? Environmental stressors: well, if you count enery as an evironmental stressor...

4) BJKlein

aging is fucked

Are you ok BJ?

I suggest a 150 and a 400 character limit, the former for a quick and dirty category, and the latter for a more descriptive but still succinct category.

That sounds like a good plan!
And also for completeness: How is your definition of aging different from your definition of senescence?

PS: Here is some of the stuff the 'experts' have come up with:

Any change in an organism over time. (Bowen & Atwood 2004)

changes with time during postmaturational life which underlie the increasing vulnerability to challenges and thereby the decreasing ability of the organism to survive. (Maroso 1998)

The collection of changes that render human beings progressively more likely to die (Medawar, 1952).

the increase of mortality q(x) for ages x after childhood where mortality is a derivative q(x) = −d ln S(x)=dx (1) where S is the number of survivors at age x. (Gompertz 19th century)

nondescript colloquialism that can mean any change over time (Finch 1990)

Edited by caliban, 18 March 2005 - 10:38 PM.

[jaydfox]

I think Medawar's is the least controversial. "Changes" could be damage, programmed, or God's will. Just "changes". As de Grey points out in the first quote I provided, there's something subtly different between a thirty-year-old and a twenty-year-old, because the former has about ten years less life expectancy, on average. That subtle difference can be termed a change.

It's also the least descriptive, but at least it's not controversial.

[caliban]

Interresting, I would think Medawar is the worst possible. Under this definition, moving from Arizona to Irak or breaking the smoke detector in your room would both be "aging".

[jaydfox]

Damn, didn't think of that. Okay, add the word intrinsic or internal or physiological, and would that suffice?

[DJS]

Progressive deleterious change at the molecular level to an organism's phenotype that leads to an increased rate of intrinsic mortality.

[vortexentity]

The progression experienced in the biological life of an organism. One of increasing simplification and specialization of genetic expression brought about mainly by the impact of environmental factors which leads to the physical death of the organism.

[susmariosep]

My definition of aging.


Aging is a biological process wherein an organism becomes weaker and weaker and loses more and more of it's life sustaining functions, resulting in its incapacity to continue at least one very crucially critical function to keep biologically alive, so that death ensues.


More expatiation:

Dying is not exactly the same as aging, but it is the terminal stage of aging. And growing is certainly the opposite of aging.

When an organism gets started in its existence which is biological life, it grows both in the quantity and quality of its component parts and its life enabling, life enjoying, and life sustaining functions.

A point in this history of growth is reached when the organism undergoes a reverse course, when it starts losing the quantity and quality of its component parts and functions. This is the period we can call broadly as dying.

Dying can happen to an organism earlier than normally expected when it suffers any destructive injury to its component parts and functions from an object outside its body causing what we call injuries or diseases to itself, or there are factors within itself which are activated that will also bring about injuries to itself, for example, with people by birth destined to obesity.

Science tells us that the component cells of the body are constantly being replaced with new ones manufactured also by itself. So in a very correct sense we can say that aging occurs when the body can no longer replace as much and as good the cells which it needs to replace to continue living.

And we can state that all life is growth, and aging being the reverse of growing, if we could maintain the quantity and quality of growth then we would have achieved the arrest of aging.

Susma

[John Schloendorn]

Looks like Finch's was not a bad bet. Though I would add the qualifier "Any change over time that somebody does not like." (Edit: in memory of BJ's post...)

Edited by John Schloendorn, 25 March 2005 - 04:12 AM.

[Karomesis]

aging= complex mechanisms that are unable to cope with the sustained onslaught of external as well as internal assaults, giving way to exponentially reproducing failures. [glasses]

[123456]

karomesis said;

"aging= complex mechanisms that are unable to cope with the sustained onslaught of external as well as internal assaults, giving way to exponentially reproducing failures."


Well said; I will second that.

[Bruce Klein]

Aging results from falling rates of repair over time.

Increase repair rates, reverse aging and grow healthier.

[caliban]

Many thanks for the input. What I'm personally looking for is a suitably succinct definition that is more that descriptive but not meta-explanatory.

Thus these don't apply

An emergent property of life where evolvability and limited resources are constraining factors.

Any change over time that somebody does not like.

complex mechanisms that are unable to cope with the sustained onslaught of external as well as internal assaults, giving way to exponentially reproducing failures

The progression experienced in the biological life of an organism. One of increasing simplification and specialization of genetic expression brought about mainly by the impact of environmental factors which leads to the physical death of the organism.

Don's definition is rather fraught with assumptions (like phenotype), but I think (strangely enough ) ) BJ and susmariosep might be on to something:

They focus on repair.

To me, that is an crucial feature, for as long as repair and replenishment are still working fine, "aging" is at most "maturation" if it exists at all.

How about:

"the progressive accumulation of primary restrictions in the regenerative capacity of multicellular organisms"

(where progressive= time-dependent , primary= root cause )

?

Help me out please?

[Bruce Klein]

1. the progressive accumulation of primary restrictions in the regenerative capacity of multicellular organisms

2. the increasing rate of primary restrictions in the regenerative capacity of multicellular organisms

3. the increasing rate of defects in the regenerative capacity of of multicellular organisms

4. the increasing rate of defects in the repair of a system

so, perhaps:

aging results from falling rates of repair over time

[jaydfox]

Well, we should be careful here. While I certainly believe that some major portion of the process of aging is due to decreasing repair, I believe that part of it is due to accumulating damage, so that even in a system that experiences no decline in regenerative capacity, damage would still accumulate and lead to pathology.

As it turns out, I believe that this accumulating damage and the reduction in repair rates are correlated, but the correlation is not 100%. In other words, even in the absence of a reduction in repair, damage would accumulate. The big question, in my mind, is whether the opposite is true. Even without an accumulation of damage, would repair rates drop with time? This is tricky, because a drop in repair rates implies damage to the repair system. So I would further subdivide "damage" into damage to repair systems, and damage that is peripheral to repair systems. Here again it gets complicated. Would repair rates fall, even if we eliminated damage directly to the repair systems? In other words, would they just get tired out by doing their job, even without being directly attacked? Or, alternatively, is there a "programmed" mechanism, either directly or by neglect, that leads to the loss of repair capacity?

So many variables, even when we remove particular pathologies (e.g. cancer) from the picture...

But I would be careful to define it solely as a loss of repair capacity. Methinks that a system which can maintain the repair capacity of youth indefinitely would still "age" and die, and not just at a constant mortality rate (which to me means it's not aging), but at an ever-increasing rate because of damage accumulation.

[Mark Hamalainen]

How do you reconcile this in the broader context of germline, cancer and laboratory-induced cell immortalization? Even a single cell without dividing can, theoretically, stay alive indefinitely if its endogenously deleterious metabolic processes are suitably counter-weighed by repair and disposal (autophagy).

A single cell not-dividing and and not-aging? I've never heard of such a cell. Nuclear mutations are a part of aging, hence cancer and otherwise 'immortal' cells are clearly aging.

I have yet to see any evidence to support the latter - that damage exists for which a strategy to repair has not evolved

mtDNA and nuclear DNA damage inevitibly accumulate as I explained in my paper. Secondary metabolic end points can take a great many forms, while some damage is specific and can be specifically repaired, much is not. 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). A great deal of damage does accumulate with age, you propose that this is entirely due to gene regulation. While that is not a theoretically impossible scenerio (if it were impossible then there wouldn't be much hope of reengineering our bodies to be able to break all secondary MEPs), I find the probability of it to be true neglidgable. Conversely, it is improbable that gene expression plays no role in aging. I believe I addressed all these points in my paper which I thought you read, if you see some logical flaw in my work please point it out to me.

there is no evidence to support that youthful repair rates are insufficient to sustain life (i.e. compare the damage accumulation in the cells of individuals between the ages of 10-20 versus 50-60)

So why do you think this?

One word: accumulation

[jaydfox]

Even a single cell without dividing can, theoretically, stay alive indefinitely if its endogenously deleterious metabolic processes are suitably counter-weighed by repair and disposal (autophagy).

Right, but with hundreds of trillions of cells, statistics is our enemy. Only one has to go down the path to cancer to kill us. Given 50,000-100,000 DNA mutation/epimutation/damage events per day, we're talking about roughly 10^21 events per year that our bodies have to deal with. Frankly, I'm impressed that cancer is kept in check as well as it is, but it doesn't take a biologist to figure out that something can go wrong without "perfect" repair systems, and there simply hasn't been enough of a selective pressure to evolve perfect repair systems. You yourself hold such as a tenet of evolvability.

I'm saying that cancer incidence rates would hardly be affected if we maintained our youthful repair mechanisms. It's reliability theory. You have a dozen or so genes that need to be (epi-)mutated, and these mutations happen at a fairly regular rate throughout life. Because of the way reliability math works, cancer rates might be negligible until we reach our 40's, and then balloon to the #1 cause of death just a couple decades later. This isn't because repair rates of cancer-causing mutations dropped. It's just statistics.

nuDNA mutations hardly accumulate with age in humans, due in large part to our very efficient repair systems. Nevertheless, damage does accumulate, and while this partially may be due to relaxed repair, I contend it is partially due to accumulation of damage that isn't repairable with even youthful repair systems. Perhaps it's because a repair mechanism itself was damaged, preventing it from doing its job properly. Perhaps it's because the damage itself is invisible to the repair system. Or perhaps it's because evolution hasn't perfected repair systems yet.

Damage accumulates, and cancer is the result. That's leaving aside all the other problems of DNA damage, as well as all the other problems of currently irreparable non-DNA damage, e.g. certain crosslinks, etc.

I contend that a biological 10-year-old would still get cancer or heart disease before reaching age 100 most of the time. A decline in repair rates may accelerate the process, but I'm not convinced that maintaining youthfulness might not increase cancer incidence rates. Some aspects of aging seem programmed, and they may be programmed to make us live *longer*. A loss of youthfulness makes us less fit against extrinsic mortality factors, but may in fact increase our resistance to intrinsic mortality factors.

You suggest that either
a) repair systems are not in sufficient abundance even during youth, or,
b) they do not functionally cover the whole spectrum of metabolically induced damage.
I have yet to see any evidence to support the latter - that damage exists for which a strategy to repair has not evolved - and whilst there is much evidence to support that repair systems enter into an age-related functional decline, there is no evidence to support that youthful repair rates are insufficient to sustain life (i.e. compare the damage accumulation in the cells of individuals between the ages of 10-20 versus 50-60)

(my emphasis, italicized portion quoted below by osiris)

I have yet to see any evidence to support the latter - that damage exists for which a strategy to repair has not evolved

mtDNA and nuclear DNA damage inevitibly accumulate as I explained in my paper. Secondary metabolic end points can take a great many forms, while some damage is specific and can be specifically repaired, much is not. 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).

Indeed, I feel this may be the case with certain types of mtDNA damage. Clonal expansion of a single mutation or deletion in mtDNA would take a minimum of 15-20 mitochondrial turnover cycles, and that's assuming that it had a 100% selection advantage. Assuming a more reasonable 20%, it may take 75-100 cycles. At 2-3 months per cycle, this means a single mtDNA mutation or deletion would take about 15-25 years to expand. With only a 10% advantage, it could take 30-50 years. So perhaps the reason that such damage accumulates measurably only in middle age isn't a sign that middle age is when repair is relaxed, but simply a sign that that's how long it takes the damage to be accumulate to a measurable level.

In other words, a 10-year-old might not have clonally expanded mtDNA mutations/deletions because those mutations/deletions are still busy clonally expanding. If it takes 50 years to clonally expand completely, then after 25 years, we'd only see half as many copies of the mutation/deletion... Half as many on a logarithmic scale, that is, which means there may only be less than a dozen mitochondria that are homochondric for the mutation/deletion, far below the detection thresholds I've seen in studies (10%-20%).

Don't get me wrong, I'm not saying that it's not possible that aging is only the result of relaxed repair. I'm just saying that there's a very weak case that this is true. I doubt there is any single cause of aging (unless you just want to attribute it to entropy, but that seems like a cop-out). Damage accumulation is probably about as important as relaxed repair, maybe less important, but maybe more important. We'll know in a few decades, perhaps a century. Until then, we need to keep our options open. SENS focusses on cleaning up accumulated damage, or at least it claims to. Digging deeper, we see that increased repair and maintenance have mischievously been hidden between the lines. What else is lysosomal enhancement, other than an increase in repair capacity? What else is allotopic expression, but a robust method of maintenance?

[jaydfox]

This statement does not mean anything. In progeroid syndromes accumulation occurs more rapidly because of insufficient repair. It follows that increased repair would reduce accumulation. It is possible that a sufficiently high rate of repair would make accumulation negligible. I repeat: there is no evidence to support that youthful repair rates, if maintained, are insufficient to prevent senescence.

Time to split hairs. Yes, I do firmly believe that increased repair rates can lengthen lifespan, perhaps significantly. However, the repair rates we seek may not have been available, even at age 10. Hence, while you say that "there is no evidence to support that youthful repair rates, if maintained, are insufficient to prevent senescence", I'm doubtful that there's much evidence that such rates would be sufficient! And you can't rely on saying that a 10-year-old has virtually no pathology, and a 50-year-old does, because both repair rates and accumulation levels are variables to consider, and both have different values at age 10 or 50. Correlation, but no proof of causation, or at least, no proof that one or the other is the primary cause.

[jaydfox]

Increase DNA repair and you prevent DNA damage accumulation. Prevent methylation from shutting down gene expression and proteins continue to be expressed normally. Maintain a high turnover of mitochondria and it ensures that zombie mitochondria do not proliferate. Ensure that lysosomal function is maintained and deleterious materials are degraded. Those that cannot be degraded can be ejected from the cell by exocytosis. Each and every age-related intracellular physiological phenomenon that becomes discovered has a solution (at least in a theoretical sense until experimentally proven). Consequently if the cell has the ability to deal with such damage, the question we must be asking is why does it not, or more importantly, why has it evolved so it allows damage to accumulate?

(my emphasis)

The question on everybody's mind! Well, maybe not everybody, since most people view aging as a fundamental and immutable property of life. But for those who can think outside the box, that's the question.

I believe, and Dr. de Grey has agreed, that it would only take a few dozen or hundred generations of evolution, using properly taylored selection pressures, to double or more the human lifespan. Evolution has had tens of thousands of generations, and hasn't gotten the job done.

So it seems that some things have been more important than maximizing lifespan. Nevertheless, we are fortunate enough to be statistical outliers, having more than twice the longevity of our closest relatives, the chimps, and thrice the longevity of larger mammals such as cows that would be predicted to live longer than us, based on metabolism alone.

Anyway, the repair rates we seek are entirely possible, but I don't think it's a matter of maintaining youthfulness. We need to go further. We need the youthful repair rates of humans that have 300+ year lifespans!

[jaydfox]

You have a dozen or so genes that need to be (epi-)mutated, and these mutations happen at a fairly regular rate throughout life.

Let me get this straight - you're suggesting that the rate of mutation/DNA damage that goes unrepaired remains constant throughout lifespan? Because if you are, I would dearly like to see the evidence.

I said "fairly regular". Not exactly regular, but fairly regular. A number that comes to mind is that the rate of 8oxodG/dG is only about three times higher in old age, compared to youth, and the accumulation of actual point mutations is only about twice is high. I'll have to dig for the numbers though, and get back to you.

At any rate (no pun intended), three times the rate of damage seems to be leading to hundred-fold and higher increases in disease rates, etc., so the disease rates aren't tied to the mutation rate at a given age, so much as they seem to be tied to accumulation of damage over a lifetime. Reliability theory predicts that a constant, or even decreasing rate of mutations could still lead to near-exponential cancer incidence rates. That mutation rates rise 100%-200% isn't the problem: the problem is accumulation over a lifetime.