November 27, 2008
Clues On SirT1 And Resveratrol Regulation Of Aging Brain Genes

The sirtuin genes activated by resveratrol seem to shift their behavior in stressed mouse cells in ways similar to how they behave in yeast. This provides an important clue about the causes of changes in gene regulation as we age. But is this an argument for taking resveratrol?

One function of the mouse version of Sir2, called SIRT1, is to regulate how genes are expressed in various tissues. Patterns of expression differ among organs--many genes that need to be active in the liver, for instance, must remain silent in the brain. By binding to regulatory regions alongside certain genes, SIRT1 helps dictate those patterns. Because SIRT1 has also been shown to participate in DNA repair, Sinclair and his colleagues wondered whether increasing DNA damage would compromise the protein's normal regulatory role, as is the case with Sir2 in yeast.

Sure enough, when the researchers treated mouse embryonic stem cells with DNA-damaging hydrogen peroxide, SIRT1 migrated away from regulatory regions of the genome and toward the many areas where DNA strands had broken. As a result, genes that were normally shut off suddenly became active. Gene expression patterns, once exquisitely fine-tuned, went haywire.

Lots of patterns of gene expression change as we age. Some of the genes that get turned on might be to try to do repair. Some are involved in inflammatory response. But the turning on of other genes might simply be mistakes that only cause harm.

"This is something that's eerily parallel to what we know in yeast," says Jan Vijg, chair of genetics at Albert Einstein College of Medicine, who was not involved in the study.

Okay, suppose the SirT1 moves to go deal with damaged DNA as we age. Suppose that leaves assorted genes no longer repressed. Then does the use of resveratrol redirect the genes back toward the genes it was originally bound to? If so, does that leave the damaged DNA unrepaired? Or does resveratrol make the SirT1 more active and therefore capable of handling more tasks at once? How can resveratrol allow SirT1 to perform both tasks at once? Anyone have an insight on this?

Connecting the dots, does the unrepression of lots of genes as SirT1 unbinds from them cause obesity?

Sirtris, a company Dr. Sinclair helped found, has developed a number of chemicals that mimic resveratrol and are potentially more suitable as drugs since they activate sirtuin at much lower doses than resveratrol. This month, one of these chemicals was reported in the journal Cell Metabolism to protect mice on fatty diets from getting obese and to enhance their endurance in treadmills, just as resveratrol does.

I am very tempted to start taking resveratrol. Haven't done it yet. I'm reluctant because I keep thinking there's no free lunch. If up-regulation of SirT1 activity will allow us to live longer why was this not selected for already? What is the cost of that higher SirT1 activity? There must be a cost or we'd already have mutations that make SirT1 more vigorous.

Does resveratrol make SirT1 keep chromatin well packed while also making SirT1 assist in DNA damage repair?

The researchers found in studies of mammalian stem cells that the protein SIRT1 controls the packaging of DNA into chromatin, thereby setting the youthful pattern of gene activity by keeping select genes switched off. In response to DNA damage, those SIRT1 proteins leave their posts to go off and assist in the necessary repairs. That change in SIRT1's job description leads to shifts in gene activity that parallel those seen in the aging mouse brain, they show. They suspect similar changes would also be found in other body tissues as well.

Again, do any readers follow the resveratrol research literature closely? What's the trade-off here when using resveratrol?

Resveratrol acts as a sirtuin activator. So does it make SirT1 do more things at once?

Resveratrol, a small molecule found in red wine, is reported to slow aging in simple eukaryotes and has been suggested as a potential calorie restriction mimetic. Resveratrol has also been reported to act as a sirtuin activator, and this property has been proposed to account for its anti-aging effects. We show here that resveratrol is a substrate-specific activator of yeast Sir2 and human SirT1.

I'd like to prevent or reverse gene regulation changes associated with aging. But can this be done with a net benefit using a single chemical compound? I'm skeptical but open to evidence.

Update: Giving extra copies of SirT1 to mice which get lymphoma causes them to live longer. But would an extra copy of the SirT1 gene cause standard lab mice to live longer? Would it cause humans to live longer?

The researchers also discovered that lab mice with an excess of SIRT1 showed fewer unwanted changes in gene expression and improved ability to repair DNA. Perhaps this is a way to slow down the aging process; by developing a drug that stimulates SIRT1, said the researchers. There is already evidence that the red wine ingredient resveratrol works via SIRT1, as do several other targeted drugs that are in various stages of development. Following a calorie restricted diet is also thought to slow aging and improve health via SIRT1.

They showed this by using mice genetically altered to model lymphoma. They gave them extra copies of SIRT1, or fed them the SIRT1 activator resveratrol, and found this extended their lifespan by between 24 and 46 per cent.

If youthful patterns of gene expression could be restored would that cause us to live longer? Or are some of the age-related changes in gene expression necessary for adjustment to accumulated damage?

What's not yet clear is how much youthful patterns of gene expression matter. Scientists not involved in the study pointed out that even if that particular aspect of aging is reversible, it is not clear that keeping gene expression young is the key to staying young.

"The paper says you might be able to maintain or go back to a younger gene expression profile, but does that mean you will be younger? You may have passed through that gate already, and you can't go back," said Dr. Stephen Helfand, a professor in the department of molecular biology, cell biology and biochemistry at Brown University.

I am especially interested in sirtuin enhancement drugs for the brain since the brain is going to be the hardest organ to rejuvenate.

Share |      Randall Parker, 2008 November 27 01:51 PM  Aging Diet Resveratrol


Comments
JP Straley said at November 27, 2008 3:21 PM:

FP asks: "If up-regulation of SirT1 activity will allow us to live longer why was this not selected for already? What is the cost of that higher SirT1 activity?"

The classic answer for this is that SirT1 is in its normal position during the age that humans reproduce. Therefore, there is no advantage (or very little advantage) to its staying in place and fostering overall homeostasis after the age of repro.

The best reason I've heard for the relatively long life of humans is that we are neotenous, that we have relatively long infancies and childhood, which is actually a result of rather slow aging and maturation processes. And neotency itself is useful because the infant is born in a rather immature sstate, with poorly connected cranial sutures, etc., which allows the big human head to make its exit through the rather tight confines of the human female. Note that in this interpretation, long life is not the benefit that fosters the trait of immaturity--it is rather better survival during the birth process.

Randall Parker said at November 27, 2008 3:35 PM:

JP Straley,

Men stay fertile decades longer than women do. So I would expect the selection for proper gene expression to last longer than age 35 in humans just due to selection on men.

dbfair said at November 27, 2008 6:24 PM:

Randall,

I think selection for gene expression in men may not be limited just by age of infertility but also by life expectancy, which I imagine for prehistoric humans was less than 35 years (http://cameron.econ.ucdavis.edu/e132/TrH.pdf says 28 yrs).

averros said at November 27, 2008 7:40 PM:

Actually, just to sustain any level of biological activity there has to be selective advantage to having this activity.

In the absense of this selective advantage the accumulation of mutaions eventually renders inoperable the genes responsible for the activity.

The level of activity is thus determined by relative improvement in reproduction rate versus genetic decay rate; since all activities advantageous to reproduction yield diminishing returns with their increase, the conserved level of activity corresponds to the equilibrium between those two processes.

Randall Parker said at November 27, 2008 8:42 PM:

Averros,

The gene is there and fully functional. There's enough functionality to keep it functioning. It is not inoperable. A mutation that made it express at a slightly higher level is an easy mutation to get. It would be selected for (or at least not get selected against) unless for effect of the slightly higher level of expression has a downside.

Could be that higher expression lowers metabolic rate a bit. There must be some cost.

gene1 said at November 28, 2008 12:07 AM:

I'm not sure why there has to be a cost - or a significant one.
Sinclair has said this year that resveratrol will soon be considered old techology. If that is true, then why not wait until his pill are on the market in 2012? I'd take resveratrol supplements if I had a serious disease or was over 65 years old. Sinclair was also taking supplements for years and says it is perfectly safe. If you think he's wrong, you may as well wait.

averros said at November 28, 2008 5:15 AM:

Randall - what I was saying is that activity of SIRT1 could be simply up to the point of diminishing returns from the point of view of reproductive advantage - both because of growing cumulative probability of death from non-age related causes, and because of aging past reproductive age. Males definitely can father children past age 35-40, but the probability of genetic defects in offspring grows rapidly after that age, lowering reproductive success.

This means that it could be that it can be increased artificially with no "cost". Could be otherwise, too - the point is that something not being fully used to the advantage of the organism does not necessarily mean that it has hidden costs. It may simply be that increasing its activity yields overall benefits that would be insufficient to conserve its activity at that level against the genetic degradation. All highly conserved genetic features are vitally important. Being able to produce offspring significantly above population reproduction rate *is not* important - most of the offpring will then die of starvation or in competition for population-limiting resources.

The notion of "fully functional" gene is somewhat meaningless - what matters is frequency of expression, which depends on activity of signaling chains regulating the expression - and that typically involves hundreds of genes. (Of course, if the gene is broken, it won't produce the functioning protein or RNA - but I strongly suspect that organisms lacking functioning SIRT1 would die quickly).

joel said at November 28, 2008 7:19 AM:

Resveratrol may be one of the most overhyped substances to come along in years.
A number of recent studies have yielded poor results. In one, mice on a normal
diet lived no longer. It helped only mice binging on high fat diets. In
another study, only mice consuming mild amounts of resveratrol fared any better
in median lifespan, the mice consuming lots of resveratrol had the same lifespan
as mice not consuming resveratrol. In a third study, tiny amounts of resveratrol
(like the amount you get from wine) was far more effective than previously thought.

Bottom line: resveratrol is not particulary effective at extending lifespan, but
could be helpful in small amounts at disease prevention. Why would we need
the 1000-fold activiation from Sirtris ? Very unclear.

Ragamuffin said at November 28, 2008 9:51 AM:

You have to learn to read between the lines of research paper conclusions and discussion. It's obvious that the more SIRT1 protein hanging around the nucleus, the more gene expression of elderly mice resembles the gene expression of young mice. The mice live longer with fewer health problems. The Sirtris formulation activates the sirtuin genes to make more SIRT1. More SIRT1, longer lifespan, more youthful gene expression. In mice.

Would you volunteer to help learn if the effect works the same way in humans? I think I would.

bdp said at November 28, 2008 12:50 PM:

What I don't understand is the lack of products AND (at least anecdotal) confirmation of "some" benefits of Reservatrol. This is not new news. It is always the miracle product - yet there is virtually no verifiable info that the stuff makes a difference. Ginko Biloba has more purported success reports. The regulations on the Supplement market are exceedingly modest - just don't sell contaminated stuff - Why don't we have 100 Jack LaLanes at 88 years of age who are now - with the help of reservatrol - able to swim the Golden Gate?

I think the concept is much more enticing than the result. Are we all Ponce de leon??
BDP

Jamie Diamond said at November 29, 2008 10:47 AM:

Resveratrol can help you to lead a long and healthy life so says Dr. Oz.
Red wine alone does not supply enough resveratrol to achieve the
full range of benefits because one glass of red wine has only about
1mg of resveratrol and you need about 250mg/day. You need to take
high potency resveratrol supplements to achieve the results documented
in scientific studies.Resveratrol Supplements can also help you control
your weight naturally by increasing energy, reducing cravings, and limiting
your appetite.According to Wikipedia, Consumer Lab, an independent dietary
supplement and over the counter products evaluation organization,
published a report on 13 November 2007 on the popular resveratrol
supplements. The organization reported that there exists a wide range
in quality, dose, and price among the 13 resveratrol products
evaluated. The actual amount of resveratrol contained in the
different brands range from 2.2mg for Revatrol, which claimed to have
400mg of "Red Wine Grape Complex", to 500mg for Biotivia.com Transmax,
which is consistent with the amount claimed on the product's label.
Prices per 100mg of resveratrol ranged from less than $.30 for
products made by Biotivia.com, jarrow, and country life, to a high of
$45.27 for the Revatrol brand.

Brent Kearney said at November 29, 2008 2:16 PM:

"Okay, suppose the SirT1 moves to go deal with damaged DNA as we age. Suppose that leaves assorted genes no longer repressed. Then does the use of resveratrol redirect the genes back toward the genes it was originally bound to? If so, does that leave the damaged DNA unrepaired? Or does resveratrol make the SirT1 more active and therefore capable of handling more tasks at once? How can resveratrol allow SirT1 to perform both tasks at once? Anyone have an insight on this?"

As I understand it, resveratrol is a "sirtuin activator", so it stimulates the creation of additional SIRT1. With more SIRT1 in the cell, more of both DNA repair and gene repression can occur at the same time.

Good question on why more SIRT1 wasn't selected already -- perhaps the additional repressive power in brain cells has adverse effects on the liver in some circumstances. Or perhaps, as others in this thread have pointed out, longevity past reproductive age wasn't selected for, and this is just one part of the shortcoming.

Lou Pagnucco said at November 29, 2008 9:28 PM:

The paper just published in the journal "Cell" is not available online, but a closely related earlier paper by Sinclair is available at:

"The role of nuclear architecture in genomic instability and ageing"
http://www.arasysperfector.com/pdf/The%20Role%20of%20Nuclear%20Architecture.pdf

I have just quickly read it, but if I understand the authors' "epigenetic balance hypothesis" correctly, DNA damage causes sirtuins to migrate away from tightly packed heterochromatin allowing it to unwind and previously silent genes to be transcribed. Furthermore, the DNA point mutations may also become sites where chromatin structure is compromised, even if the DNA is repaired properly, allowing genes near the repaired sites to also become active. These changes (I think) are essentially irreversible, and explain why gene expression becomes more variable in aged tissue - i.e., epigenetic drift.

I am curious whether inter-species comparisons indicate that longer lived species have more sirtuin/sirtuin-activity than shorter lived species.

In said at November 30, 2008 10:15 AM:

Perhaps SIRT1 activation didn't have the positive benefits in people living a paleo lifestyle as it has for those living unnatural modern lifestyles.

The modern lifestyle tends to promote silent inflammation. More active SIRT1 may have little effect (hence didn't get selected for) when there is little silent inflammation.

Randall Parker said at November 30, 2008 10:55 AM:

In,

Interesting speculation. We ought to be able to test that by putting people on different diets to see if we can get the same result as resveratrol without taking resveratrol. So far my impression from reading reports on the research in this area is that only calorie restriction will produce a similar result.

jon said at December 1, 2008 5:03 PM:

Natural selection does not operate to benefit the individual. In an environment that will only support a given number of individuals, mutations that result in a shorter lifespan for the individual might be beneficial to the host population by increasing the overall rate at which genes are passed through the population through sexual reproduction.

Barry Kearns said at December 1, 2008 5:20 PM:

"If up-regulation of SirT1 activity will allow us to live longer why was this not selected for already?"

Past optimal breeding age, longer life tends to be a net drain on a stressed species as a whole. Scarce resources are thus being consumed by those who are no longer propagating the genome, at the expense of those who could be. If anything, I would expect that this would represent a stronger selection effect for down-regulation than up-regulation in the ages when proto-humans faced severe survival pressures.

Down-regulation would then act as a natural "suicide gene" expression for the elderly, freeing up scarce resources for the breeding population. The current low levels of regulation would thus be an expected outcome.

Nowadays, we don't face the same selection pressures, but we haven't been in that regime long enough for substantial selection of this type to take place.

I'm cautiously optimistic about this.

Bill Quick said at December 1, 2008 5:40 PM:
So far my impression from reading reports on the research in this area is that only calorie restriction will produce a similar result.
Look into studies done on the effects of ketogenic low-carbohydrate diets on Sirt expression and insulin modulation. CRON, resveratrol, and ketogenic lo-carb all have quite similar effects.
Doug Collins said at December 1, 2008 5:59 PM:

The selection theories that have been mentioned seem a little simplistic. In human populations, the effect of social structures and dynamics are likely to be as important as individual traits. Primitive people lived or died by the tribe. Banishment from the tribe was a death sentence.

In the subsistence societies of the Kalahiri, the old men and women are left behind with the children as the younger men and women take the cattle to distant waterholes during the drought season. In extreme starvation conditions, the old men will even begin to lactate. Obviously, in this case longer life for the old-especially if they have low dietary requirements- results in higher survival rates for children.

In slightly more advanced societies, the old serve as a repository of information and skills. This had to be vital in a pre-literate society.
Their survival value to the group would be directly proportional to the length of their lives and the clarity of their memories.

People aren't mice. And their evolutionary dynamics are likely to be a lot more complicated.

frege said at December 1, 2008 6:33 PM:

Your item "Resveratrol acts as a sirtuin activator" is not supported by the paper you link to. The excerpt below is from the first paragraph of the discussion section of that paper. These authors were reporting that resveratrol did not activate sirtuins in vivo which was "[i]n contrast to the prior report." There may be other evidence, but this paper does not say what your header suggests.

"The biological activities of resveratrol have been noted for at least 20 years (47). Resveratrol has been proposed to have wide ranging effects, including proapoptotic, fungicidal (48), chemopreventive (49), and antioxidant (50, 51) properties. Most recently, resveratrol has been suggested to activate sirtuins both in vitro and in vivo and to enhance longevity in yeast, worms, and flies (33, 34). In contrast to the prior report (33), we find that treatment of yeast cells with resveratrol failed to cause any of the phenotypes expected upon activation of Sir2, and activation of Sir2 orthologs by resveratrol in vitro appeared to be an artifact, as it was specific for substrates containing the non-physiological, fluorescent Fluor de Lys moiety."

http://www.ncbi.nlm.nih.gov/pubmed/15684413

jon said at December 2, 2008 1:04 PM:

"the old men and women are left behind with the children"

They could certainly use that time to educate the children, but it would also be beneficial if the adult left behind was young enough also able to provide defense against animals or perhaps a lone human intruder. One can argue either way, but the evidence suggests that humans did not usually live much past child rearing age. Fact is, they could have evolved to remain physically strong for a longer time, but they didn't. The amount of intelligence that humans have is so great that evolution must have been very rapid, and so populations with a shorter time between generations and more focus of energy on fast reproduction would have an advantage in developing the genetics of intelligence.

Barry Kearns said at December 3, 2008 11:42 AM:

"The selection theories that have been mentioned seem a little simplistic. In human populations, the effect of social structures and dynamics are likely to be as important as individual traits. Primitive people lived or died by the tribe." -Doug Collins said at December 1, 2008 05:59 PM

Compare the amount of time that humans have had societal structures of this type, with how long the sirtuin structures have existed as a whole. The former is utterly overwhelmed by the latter in terms of time for selection effects to take place. The down-regulation selection advantage I discussed would have been in effect for significantly longer, throughout the entire chain of ancestral species. The relative eye-blink of time during which human societal effects have been acting is thus unlikely to serve as a strongly overriding factor. Once the down-regulation has been successfully selected-for, it would take a substantial overriding later advantage in subsequent up-regulation to undo this (not to mention sufficient time).

I see no such overriding advantages to the species from a genetic standpoint in lengthening the lifespan of individual members beyond optimal breeding ages.

"History" may have "begun" with the advent of society and communications, but genetic selection provided a legacy long, long before "history" began.

Randall Parker said at December 3, 2008 6:55 PM:

Barry Kearns,

But optimal breeding age range depends on how rapidly our bodies wear out. If we age less quickly then we'll stay fertile longer.

In order for longer lasting parts to have been selected against there had to be short term advantages of parts that wear out more quickly. What short term advantages come from having lower sirtuin activity? If advantages didn't exist from lower sirtuin activity then we'd have more sirtuin activity.

Lou Pagnucco said at December 4, 2008 7:46 AM:

Randall,

Although the press release doesn't mention it, I believe that the paper cited attributes "noisy" genetic transcription in aged cells to accumulating chromatin damage which compromises the cells' nuclear scaffolding.

According to online literature, neurons are exemptions. Old neurons retain their nuclear integrity. This begs the question - Are they less likely to suffer DNA damage and mutations?

Furthermore, a couple of other papers suggest that this chromatin damage correlates with insulin signaling. If so, does insulin signaling promote DNA damage, in turn causing chromatin instability? It may be worth noting that resveratrol affects insulin signaling independent of its sirtuin role.

Kevin Devereaux said at December 4, 2008 8:26 AM:

It seems obvious to me why additional SIRT expression was not evolutionarily advantageous... it keeps you from putting on weight! In our current calorie overloaded society that is a good thing. For a caveman, not being able to put on the pounds when the hunting was good would lead to death by starvation when food was scarce.

Barry Kearns said at December 4, 2008 1:00 PM:

"But optimal breeding age range depends on how rapidly our bodies wear out. If we age less quickly then we'll stay fertile longer." - Randall Parker said at December 3, 2008 06:55 PM

This doesn't necessarily follow. The genetic triggers for the onset of menopause, for instance, might be unrelated to total cellular damage, and thus up-regulation of SIRT expression might lead to a longer total age without necessarily extending the time window of fertility.

"In order for longer lasting parts to have been selected against there had to be short term advantages of parts that wear out more quickly. What short term advantages come from having lower sirtuin activity? If advantages didn't exist from lower sirtuin activity then we'd have more sirtuin activity."

I don't think you're following the logic here. The advantages upon which selection acts are advantages at the SPECIES level (or to be more precise, at the genome level), not at the individual short-term advantage level. Some short-term individual advantages are also genomic advantages, and they are thus selected-for... but not purely because they were individual advantages.

Take any given genetic pool, and divide it... say, geographically. Assume that initially on each side of the divide, you have members with a long total lifespan, but a limited window of fertility, and scarce resources for population support. If on one side, there is a mutation which tends to act as a "suicide gene" beyond the window of fertility, the emergent effect on the population pool as a whole will be for more resources to be available to support the breeding-age population, and thus the population as a whole will become more robust.

There will be a higher total number of population members in prime physical shape, as well as a much higher average physical fitness. Thus, if these two groups were to compete over the same territory, the more robust group would be more likely to triumph at the expense of the original group... even though, as individuals, their total lifespans are shorter.

Selection only "cares" about the success of propagating a given genome. Anything that gives a differential edge to success at that propagation will tend to be selected, even if it "costs" the individual member. In this case, the genome propagates more successfully due to shortening the post-breeding lifespan of the individuals.

Randall Parker said at December 4, 2008 7:44 PM:

Barry Kearns,

Your use of the term "species level" and then "genome level" as meaning the same thing does not make sense to me. Individual genomes are not species. They are just individual genomes.

Yes, of course, I understand that selection can cause suffering or shorter lives for individuals. Selection is for reproductive fitness. But you are not answering the question when you say:

In this case, the genome propagates more successfully due to shortening the post-breeding lifespan of the individuals.

Certainly lots of mutations can increase reproductive fitness in ways that shorten lifespans. But in order for a sirtuin down-regulating mutation to boost reproductive fitness while decreasing lifespan there has to be a mechanism by which it happens. So far only Kevin Devereaux has suggested a mechanism.

Again, if turning up sirtuin expression extends lifespan then it must do so at some expense. Does it slow us down running? Make us less able to ward off infections? Make us store less fat for lean years? Even if it reduces fat storage and therefore would have been selected against why couldn't another mutation have increased fat storage even with lots of sirtuin expression?

Lou Pagnucco asks an important question:

According to online literature, neurons are exemptions. Old neurons retain their nuclear integrity. This begs the question - Are they less likely to suffer DNA damage and mutations?

Neurons differ in other notable ways. In particular, they've got mitochondria that are far from the nucleus (though they must have some mitochondria closer to the nucleus). Maybe in a neuron the nucleus is less stressed by free radicals than in other cell types. Also, neurons have helper cells around them. Maybe the helper cells take on some of the oxidatively stressing tasks so that neurons get less oxidatively stressed that way. Of course, that just shifts the aging problem to the support cells.

Lou Pagnucco said at December 5, 2008 9:30 AM:

The earlier Sinclair paper -
"The role of nuclear architecture in genomic instability and ageing"
http://www.arasysperfector.com/pdf/The%20Role%20of%20Nuclear%20Architecture.pdf
- seems to attribute the chromatin/nuclear architecture changes to undirected noisy metabolic events resulting in sporadic DNA damage and mutation - at least, that's my layman's interpretation.

The following article hypothesizes that what superficially appear to be "damaging" cellular events (including changes in nuclear architecture and DNA strand breaks) are actually orchestrated by programmed differentiation. See:
"Is caspase-dependent apoptosis only cell differentiation taken to the extreme?" -FASEB Journal, Vol. 21 January 2007
http://www.fasebj.org/cgi/reprint/21/1/8.pdf

Possibly, the chromatin condensation observed in the Sinclair papers is purposefully (but stochastic and non-uniformly) driven by a differentiation program that exploits metabolic noise the best it can?

Barry Kearns said at December 5, 2008 11:05 AM:

"Certainly lots of mutations can increase reproductive fitness in ways that shorten lifespans. But in order for a sirtuin down-regulating mutation to boost reproductive fitness while decreasing lifespan there has to be a mechanism by which it happens. So far only Kevin Devereaux has suggested a mechanism. Again, if turning up sirtuin expression extends lifespan then it must do so at some expense. Does it slow us down running? Make us less able to ward off infections? Make us store less fat for lean years? Even if it reduces fat storage and therefore would have been selected against why couldn't another mutation have increased fat storage even with lots of sirtuin expression?"

I have suggested such a mechanism for boosting reproductive fitness. In resource-constrained environments (only enough food per year to support a population of size X), a shortened lifespan post-reproduction frees up resources which would otherwise be consumed by individuals who are no longer successfully propagating their genome. Thus, the "expense" of up-regulation of sirtuin expression in resource-constrained environments is to have a smaller pool of breeding population members. This makes the population pool more vulnerable when events happen which increase infant mortality rates (famines, floods, influx of new predators, etc).

If such events were to hit an area with two population pools, one up-regulated and one down-regulated, the down-regulated pool would have a repopulation and fighting advantage when it comes to claiming territory. The population pool which has a down-regulated sirtuin expression has a higher fraction of their population that is of breeding and fighting age, and is younger (and thus more fit) across the board.

Beyond breeding age, individuals are generally a *cost* to their population pool. The farther away from breeding age, the greater the cost/benefit ratio becomes. Thus, a genetic change that frees up those expenses via some kind of post-breeding-age "suicide switch" (and allows the remaining pool to thus expand to use that resource capacity) is an increase in reproductive fitness.

Randall Parker said at December 6, 2008 9:28 PM:

Barry Kearns,

Okay, I get it. You say:

a shortened lifespan post-reproduction frees up resources which would otherwise be consumed by individuals who are no longer successfully propagating their genome.

...

Beyond breeding age, individuals are generally a *cost* to their population pool.

There's actually historical evidence to the contrary. A Finnish study published in Nature in March 2004 found that grandmothers boost the number of grandchildren they get when grannie lives longer:

Using complete multi-generational demographic records, we show that women with a prolonged post-reproductive lifespan have more grandchildren, and hence greater fitness, in pre-modern populations of both Finns and Canadians. This fitness benefit arises because post-reproductive mothers enhance the lifetime reproductive success of their offspring by allowing them to breed earlier, more frequently and more successfully. Finally, the fitness benefits of prolonged lifespan diminish as the reproductive output of offspring declines. This suggests that in female humans, selection for deferred ageing should wane when one's own offspring become post-reproductive and, correspondingly, we show that rates of female mortality accelerate as their offspring terminate reproduction.

One hypothesis for why: Grannie takes care of the kids, freeing mom up to do more food-producing and other activities.

The fact that grandmothers live well beyond their reproductive years suggests a selective pressure is at work.

The evolutionary biologist has also used this historical data set to ponder the conundrum of grandmothers. That is, why human women often live long after they are able to reproduce (on average around the age of 50), unlike almost all other animals. "If your ultimate purpose in life was to create as many offspring as possible or pass off as many genes," Lummaa says, "it's kind of strange that human women stop halfway."

One possible explanation is that having a grandmother around somehow improves the reproductive potential of her grandchildren. In fact, that is exactly what the researchers found when they reviewed stats on 537 Finnish women who had a combined total of 6,002 grandchildren. Adding in data from more than 3,000 French Canadians (who had a modest 100,074 grandchildren) confirmed that having grandma around to help enabled younger women to have more children sooner and with improved chances of surviving into adulthood. "That suggests that perhaps one reason why women do carry on living is because they are able to help," Lummaa says.

Of course, studying humans requires teasing out the confounding cultural effects. For example, the Finnish data indicated that child mortality was much higher in mainland towns than on the islands of Finland's Archipelago Sea. This can be traced back to the fact that mainland women were responsible for farm work, leading to earlier replacement of mother's milk with cow's milk. "That led to infections," Lummaa notes. "In the archipelago this was not the case." Birth rates in both areas also tended to cluster roughly nine months after the period when Finns traditionally married: after the fall harvest.


Barry Kearns said at December 8, 2008 9:26 AM:

Randall,

What you need to keep in mind is that these sirtuin structures are very, very old.... much older than humanity itself. Any species can (and should) benefit from the type of down-regulation I've discussed if they are resource constrained (and a great many animal species are, as they tend to expand population size until they hit such a constraint).

Accordingly, the "suicide switch" could have come into effect very far back in the chain of ancestral organisms. Once in place, it would take a compelling reproductive benefit to UNDO the effects that were already in place. The amount of time that human societal structures have been in place (and the species has been able to take advantage of them) has been relatively miniscule from the perspective of major genetic selection effects.

Humans began overriding the effects of natural selection as soon as society created enough abundance to shelter and protect the weak and infirm, allowing them to pass on their genes. This is not a bad thing, of course, but the path of natural selection has been fundamentally altered for humans from that point forward. I would contend that the rise of societies in humans, particularly agrarian ones which raise livestock and allow a substitute for mother's milk, largely coincides with that divergence from the "natural" evolutionary path.

To see the effects of this, we should concentrate not on human societies, but on the animal kingdom where the sirtuin structures have undergone down-regualtion or up-regulation selection pressures for a long, long time. In those cases, I think the mechanism I proposed largely holds.

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