99 replies to this topic

[kevin]

(GG) Comment on aging theories in general

I hope this doesn't add to the mess Ocsrazor..

In the discussion of aging mechanisms with a great deal of attention being given to telomeres and CR/mitochondrial function, I wonder why the following information hasn't been more visible as it seems to me to be quite relevant. Perhaps one of you might shed some light as to why I haven't read about this anywhere else...

Back in Sept 2001 I was just beginning to 'surf', and I did a search for websites that had to do with scientific 'breakthroughs' and I came across a press release that made me excited (in hindsight rather prematurely..) that an incredible discovery had been made. A Dr. Robert Costa, at the University of Illinois, had been working on a fairly ubiquitous gene family he called the Fox genes since 1993, and found that one in particular, the FoxM1B gene was involved in the healthy replication and turnover of cells. He called it unabashedly, the "Fountain of Youth" gene. He found that diminished expression of FoxM1B was associated with lower turnover of cells in tissue. In his experiment, the livers of aged mice, when fitted with a promoter designed to enhance expression of the FoxM1B gene, had organ recovery similar to that of younger mice, when given a partial hepatectomy.

http://www.eurekaler...a-urf092401.php

A second press release a year later describe how he built upon his initial observations with a mechanism for how the gene might exert it's influence.

http://www.eurekaler...a-hpi122402.php

As it seems the gene has some effect on the rate of mitosis, maybe it can affect the aging through the dual effect of timing and direct action. I'm going to try to dig up a little more info and I'll post them if there's anyone interested...

Edited by ocsrazor, 03 March 2003 - 04:03 PM.

[ocsrazor]

(XX) Comment on the discussion in general or another point of interest

Hi Gang,

Lazarus Long and I had an interesting discussion about biological timing here which I moved to its own thread: Biological Timing. This may impact on aging through the alteration of the timing of sexual development and maturation.

Best,
Ocsrazor

[ocsrazor]

(GG) Comment on aging theories in general

Hi Kevin,

No one has really talked about cell turnover specifically yet here and it is definitely applicable. I tend to see this as another one of those mechanisms that go haywire as we get older. From the a quick read, the researcher seems to think that this gene is becoming nonfunctional with age, which he suggests may be be due to DNA damage. This may also be tied into the loss of hormonal control of cell division with age as well. There is a tight balance between having runaway cell division and getting cancer on one hand, and maintenance of the organism on the other. Please post additional research if you find it.

Best,
Ocsrazor

[Lazarus Long]

General Comment on Aging

This was actually a post in the thread that started this whole area of discussion. It was by Another God and I think it deserves to be placed in this one because it addresses succinctly various areas of conflict, confusion, and question.

Well, we can work from the fact that the Body releases certain chemicals (hormones, enzymes..whatever) as it needs them. More testosterone, less estrogen etc at specific ages.

The body knows, as you said, when it is in puberty. It knows when to go through menopause (though that may be simply triggered by the end of Eggs.) It knows when to harden your bones (from the softer, more numerous Baby bones), it knows when to make u grow. It knows when to make u stop growing. It knows when to get hairy.

So, obviously the body knows how old it is. No doubt, at these particular ages, genes are turned on, and those genes cause hormones to be produced in excess (or, some genes are turned off, and some hormones etc are stopped being produced). But....BUT....what is it that figures out when it is time to turn on/off those genes?

There MUST be a biological clock. Perhaps it is a slow build up of a particular chemical (but surely such a thing would be detectable? Take a cellular sample from a baby and a cellular sample from an octagenerian and look for the difference in chemical composition), perhaps it does have to do with genetic dmg? (But such a thing really isn't....definite enough. Some cells get dmgd, some don't. There is no simple, exact clock built into the random bombardment of genetic dmg.)

While genetic damage, cellular dmg etc (as result of Free Radicals, radiation etc) is most definately a part of aging, I am not convinced that this is the sort of method that something would evolve to use as a determination of age.  

As should be made clear by all the examples of age related phenomenon above, it is vitally important for the body to know how old it is. An organism as advanced as Mammals MUST (tentatively) have a definate biological clock with which to measure this advancement through time.

Towards developing this better understanding of the crossover relationship I would like some help at

Biological Timing

[ocsrazor]

(GG) Comment on aging theories in general
Hi Gang,

Tying these ideas together with that of evolution and development for Lazarus. What the body as a system seems to recognize is certain developmental landmarks such as: this tissue touched that tissue so it is time to stop growing, this structure is yeah big so it is time to start producing this hormone, or I'm low on eggs so it is time to start menopause. All timing is relative to other structures or systems in an organism. I would think it would be unlikely that the body would "know" its age in an absolute sense, just that it knows when to start or stop things according to what is happening in the rest of the system. In the case where there are clocks they don't have extremely long memories and can often vary their timing dependent on what is going on in the local environment.

In the case of aging, there doesn't seem to be any landmarks to clock off of. Menopause is the one striking example of difference to this statement. A low amount of eggs seems to trigger the last developmental program (hormonal changes, etc.) in women.

Best,
Ocsrazor

[caliban]

XX- Summary of the first month of discussion:

---

I : What relationship exists between the damage- based and the program based theories?

From early on, the debate centred around the core issue that was set out in the introduction:
Ocsrazor made a strong case against the existence of an aging program.
Following "Evolutionary Biology of Aging", by M.R. Rose, he is arguing from a position that discounts the existence of a life-span controlling program. He does purport however, that species are only designed to last for as long as they need to reproduce themselves. Ocsrazor was presented with three of the obvious questions (the forth one being on salmon, the fifth -and to me the most striking- one on probabilities) on this matter:

1) animals of different species have different life spans
Ocsrazor argues that this is due to differing sexual cycles and different quality protection and repair systems.

2) telomeres seem to regulate life span
Ocsrazor sees telomeres not as an "biological clock" but just one other system that different animals have different protection systems against.

3) there are hormones and other bio timers that seem to regulate our life cycle
This discussion was largely branched out into
-> Biological Timing
-> How does the body know its age?
-> Cell Clock Discovered,

---

II: Evolution

From this point, the discussion inevitably moved on to the wider picture of Evolution.
Remarkably, there seemed to be an almost casual agreement that there is no selection pressure that favours aging. However, Doubting Dydimus picked the question up from another angle: what is stopping a species from evolving adaptations that prevent ageing and extend life? In response to this, OcsRazor first seemed to favour environmental challenges over the disposable soma theory but later also stressed the importance of antagonistic pleiotropy. Regrettably, the debate has not progressed since this point, but the suggestion to open a separate thread on this has much merit.

---

III: Preliminary result

This was the main discussion so far, centred mainly on the point of "is there a program for aging?"
It seems, that at this stage of the debate we can summarise:

There seems to be no program for aging, nor is there an evolutionary selection pressure to have one.
However, a species is only "designed" to survive as long as necessary for successful reproduction.

Assuming that this assumption is correct, (and there are still some points that might be raised on this) what follows from it?
Firstly, Ocsrazor and caliban pointed out that this answer has certain political and ethical implications let alone medical ones:
On the one hand, it could be argued, that since there is no "life clock" there is no divine predestination that humans should only life a certain maximal lifespan. On the other hand, the non-existence of such a clock makes it much harder to find and deactivate a central trigger for aging.
Since the first point is rather moot and might not appeal to naturalist philosophers anyway, I would respond to a question by Kissinger that in conclusion this finding is rather BAD NEWS. [huh]

---

IV: Damage factors

However, if we accept this statement, as true, the focus ought to lie on the damage - based theories of aging, striving to identify the mechanism most crucial to human aging.
Wannabe identified one factor as dehydration of the cell membrane. However, Ocsrazor argued that cell membrane damage and crosslinking is a symptom of aging rather than one of the underlying causes. In his view, structures to investigate as being involved in the aging process ought to be those, which cannot be repaired or are not renewed on a regular basis. (Such as DNA or neurons) In this context, he identified free radical damage in/from mitochondria as one key factor. Accordingly, caliban presented the free radical theory of aging but argued, that it is today necessary to expand and modify this theory.

---

---

This as a summary of the first month. Inevitably, things might slow down a bit, now but as the above shows, there are numerous points that might still be addressed.

While all contributions as outlined in the introduction are and remain welcome, I would suggest, that in the next chapter of this debate, we investigate some of the damage- based theories and undertake to chart their interaction.

---

At this stage I would like to thank all authors for their excellent contributions:
In order of appearance:

ocsrazor, who with his firm expertise and his constant involvement served as the main contributor and kindly agreed to moderate in my absence.
wannabe, who raised an interesting point on cell membranes and did not falter in following it up.
Kissinger, who despite having doubts about his own position did not hesitate to contribute with some excellent questions and observations on the possibility of an aging program.
ImmortalPhilosopher, who succinctly pointed to telomeres as an important facet of the debate.
Doubting Didymus, who raised an extremely interesting point about evolution. Although the ensuing debate with ocsrazor sometimes was more a clarification of views and sometimes left the topic a bit, it is one of the gems of this first month with some open issues yet to be resolved.
BJKlein, who helped all by pointing to Ben Best's Mechanisms of Aging as an invaluable resource.
kperrott, who with his observations on sexual maturity opened a whole new side to the program vs. damage debate. His other contribution about the FoxM1B gene still remains to be discussed fully.
Lazarus Long, who with his usual style and panache not only instigated a number of spin-off topics but crucially reminds us, that in the light of the evidence, it would be rash to talk damage only and discount the existence of an biological clock.

Many thanks to you and all who followed this topic. If the coming months maintain the standard and velocity of the first, we will have produced a truly worthwhile resource in the end!

[ocsrazor]

(GG)New information on Damage Mechanisms and Stem Cell involvement in Aging

Today I attended a talk by Dr. Marie Csete of Emory University who is working towards understanding the relationship of oxygen levels and cell redox state to stem cell proliferation and differentiation. She specifically works with neural and muscle progenitor cells. Both these cell types are finely tuned to the amount of oxygen present during development and will produce different cell types based on the oxygen concentration. She has already shown that muscle stem cells (satellite cells) in the adult can also produce the adipocyte (fat storage) cell type and that this is highly dependent on the level of oxygen radicals present. From her data it seems as though the loss of ability to control oxygen and free radical species with age is pushing muscle stem cells towards producing the adipocyte cell type, which may account for the accumulation of fat in muscle tissue with age. She is now pursuing similar experiments with neural stem cells.

Take home messages
[>] a strong anti-oxidant system may help keep you thin with age
[>] stem cells are finely tuned sensors of oxygen and redox state and respond to changes with gene regulatory mechanisms
[>] the oxygen and free radical control system is probably failing with age, changing the cell types that stem cells are producing

Best,
Ocsrazor

[kevin]

BB) Program Theory: Reproductive Tissue Regulates Livespan

I had earlier posted a link to a paper describing the effect of reproductive tissue signals on lifespan of the nematode C. Elegans as described by C. Kenyon.

Three years ago the lab reported that signals from the germline – the source of sperm and eggs – shorten lifespan, while signals from the somatic gonads – the part of the reproductive tissue that surrounds the germ cells – lengthen lifespan, with the two systems able to send equal but opposite signals. They showed that removing the precursor egg and sperm cells increased lifespan, but not because of sterility which some researchers had speculated would boost longevity.

Stem cells for eggs and sperm also control aging in roundworm

---

EE) Evolution and Aging: 'senescence as an adaptation' under the pressure for population diversity

I found an interesting essay that supports the idea of programmed aging by describing 'senescence as an adaptation' under the pressure for population diversity. It takes prevailing theories of the cause of senescence, The Disposable Soma, Antagonistic Pleiotropy, and Mutational Theories and tries to use them to explain the effects of CR and finds them all wanting. He uses this as well as other arguments to support the idea that aging is under the control at least to some degree, of our ability to reproduce.

http://mathforum.com...h/evol-cr3.html

Putting together the fact that Calorie Restriction down regulates fertility while up regulating repair in nearly all observed organisms, I wonder if somehow the insulin pathway or some other mechanism is linked in some manner to the production of the 'aging' steroid that Kenyon's research proposes exists.

The phenomenon of polymorphism in genetics with the Major Histocompatibility Complex is an example of evolution which protects the survival of the species without regard for the individual. It may be that when resources are high and the survival of offspring is relatively high, we are allowed to survive just long enough to bring that generation to independence and then the pressure for genetic diversity encourages the "been there.. done that" DNA to shuffle off this mortal coil to become the fertilizer required for the next round. A down regulating effect on reproduction when resources are scarce is reasonable as offspring would be less likely to survive and survival of the species is better served by placing energy into keeping the current generation around to wait for better times. As we filled our evolutionary niche, was the length of our lifespan determined by the push/pull of a cycle in the availability of resources in our particular niche and does the pressure for genetic diversity play a stronger role than currently thought?

It may be that the reproductive tissue, senses by some mechanism the level of energy available for reproduction. If the energy falls below a certain level, the reproductive tissue modifies the signals it sends out, encouraging the survival of the individual. After sexual maturation a constant high level of available energy tells the reproductive tissue to adjust the levels of signal to favor senescence. Regardless, this can't be the whole story and other factors must play a role or the worms would have been immortalized, but the possibility of a tie-in is intriguing.

Edited by caliban, 16 March 2003 - 01:49 PM.

[ocsrazor]

Hi Ken,

BC) Comment on Program Theory: Reproductive Tissue Regulates Livespan

Kenyon's paper doesn't really give any evidence for programmed aging, but does highlight that the developmental proces is a good predictor of total age of an organism. This shouldn't be confused as programmed aging though, it is simply that the length of reproductive period is defined by the genotype and the aging process is an unraveling of the mechanisms of development. If you grow identical organisms under identical environmental conditions they will have nearly identical failure rates of all the various systems involved in aging.


EE) Evolution and Aging: 'senescence as an adaptation' under the pressure for population diversity

I skimmed the Mitteldorf paper, and it is extremely sloppy. There are some fundamental errors in some of his statements, which makes me wonder if he has really read the literature (suprising from someone who is a post-doc in evolutionary biology at a major university) These include:

[>] He states that there is no ironclad link between fertility and senescence - this is absolutely false. There is an extremely large body of work over 40 years proving the existence of the link.

[>] He has completely failed to understand the significance of Michael Rose's data for antagonistic pleiotropy, and has confused single gene studies with the complex interactions of the genotype as a whole.

[>] Completely confusing the evolutionary reasons for the existence of telomeres - It is very clear from the literature that they evolved as a protective mechanism, not as a timing mechanism.

[>] This one really blew my mind. Senescence is ABSOLUTELY a gradual process in higher organisms and does not have a sudden onset in middle age as Mitteldorf states.

With the number of errors in this paper, it makes me suspect that this person will be completely ignored by the field.

I am somewhat out of touch with the literature and Kenyon may be trying to build a case for adaptive aging, which is going to be difficult to say the least in the face of the weight of evidence, but as I said above her recent data doesn't really make a convincing story for aging as an adaptation.

---

FF) disposable soma vs. antagonistic pleiotropy

Also, Caliban, just to let you know, I see the disposable soma and antagonistic pleiotropy theories as two aspects of the same thing, and don't really regard them separately.

Best,
Ocsrazor

Edited by caliban, 16 March 2003 - 01:48 PM.

[caliban]

FF) disposable soma vs. antagonistic pleiotropy

ocsrazor :  (...) I see the disposable soma and antagonistic pleiotropy theories as two aspects of the same thing, and don't really regard them separately.

I did not mean to imply otherwise. To what extend would you regard them as aspects and not just as semantics?

[caliban]

EE) - Diversification Pressures

kperrott: pressure for genetic diversity encourages the "been there.. done that" DNA to shuffle off this mortal coil

This seems a recurring assumption in certain evolutionary debates on aging. We have touched on this before and will most likely re-examine it again, but I would like to stress that in my view there is no logic in postulating evolutionary pressure on the successful organism to diversify. There is no "been there, done that" with a negative undertone. On the contrary, in a stable environment, "been there, done that" is a mark of success, an achievement that ought to be protected from the detrimental aspects of the reproduction lottery. For evolution, there are very few levers for "survival of the species" considerations.

[kevin]

EE) Genetically determined reason for aging as proposed by Weissman.

This discussion on the causes of aging supports the idea of a genetically determined reason for aging proposed by Weissman.

He describes how the rate of evolution, focus of natural selection and genetic diversity all play a part in promoting species level characteristics that enhance the transmission of traits beneficial to the survival of a species as well as describing many thought provoking aspects to all theories of aging.

http://www.azinet.co..._Evolution.html

Edited by caliban, 17 March 2003 - 03:20 AM.

[ocsrazor]

FF) Disposable Soma and Antagonistic Pleiotropy
Caliban- I see the DS theory as a global result caused by a set of mechanisms which includes AP. Just different levels of detail of the same thing.

I went back and looked at your summary post and realized you were stressing my environmental challenges focus as separate from DS theory, but you didn't mean that DS was separate from AP. I hope I made clear the connection between environmental contstraints and these two theories. [?]

EE) General Evolution Comment in diversification pressures
Also, to note the flip side of your comment to Kevin - in an unstable environment, genetic diverstiy is extremely valuable. It all depends on the environment you are in. In the long run genetic diversity usually wins out because environments don't stay the same for long on the gelological timescale - that is why sex has been so successful as a strategy, despite some of the consequences especially for simple organisms.

EE) Evolution of Aging
Kevin (sorry about the name mixup [blush] ) Certainly Kenyon's work is extremely interesting in discovering the mechanism by which the reproductive period is shortened or lengthened (which consequently acts as a predictor for total length of lifespan) If we know how the system is regulated, we may be able to provide the control signals that are absent or damaged with age, which at the very least might be able to change the trajectory of aging into a longer arc.

I skimmed the Goldsmith article, and it seems like a good review of the field, but from reading his conclusion, it looks like he may be confusing programmed aging with control of reproductive fitness - a common error.

Best, Ocsrazor

Edited by caliban, 17 March 2003 - 03:22 AM.

[caliban]

AA) Human stem cells as targets for the aging and diseases of aging processes
We have touced on this already:

Human stem cells as targets for the aging and diseases of aging processes
James E. Trosko
Medical Hypotheses (2003) 60(3), 439–447

Summary: While many theories have been proposed for the aging process, and many debates on the matter of aging and the diseases of aging being either the result of the same or independent processes, most have not considered humans as a hierarchical system made up of cybernetically interacting levels of organization.

To understand the aging process and the diseases of aging, one must view the human as the result of the total genomic DNA in the single fertilized egg that proliferates, differentiates and develops into an individual of about 100 trillion cells, organized by different cell types (pluri-potent stem cells, progenitor stem cells, terminally differentiated cells) into multiple tissue, organ and organ systems which interact with each other via endogenous factors and with exogenous factors.

Our hypothesis is that both aging and diseases of aging are dependent of the normal functioning of the pluri-potent stem cell pool. Specifically, the concept involves the cybernetic feedback between the ‘quantity’ of the stem cell pool in each tissue niche with the ‘quality’ of the stem cells in the pool. The process of gap junctional inter-cellular communication (GJIC), which has been implicated in the evolution from the single cell organism to the multi-cellular organisms, requiring growth control, differentiation, apoptosis, adaptive response capability of differentiated cells and senescence, is speculated to be a shared mechanism in stem cell biology and in many chronic disease processes (teratogenesis; carcinogenesis, atherogenesis, diabetigenesis, etc.).

Specifically, stem cells are assumed to be ‘immortal’ until induced to express their connexin genes and have functional GJIC, at which time they can differentiate and become ‘mortal’. As long as the stem cells are communicating with their differentiated daughters via some extra-cellular soluble negative growth factor, the homeostatic control of their growth and differentiation is maintained for the organism. However, if the stem cell pool is depleted by any process, replacement of tissue due to wear and tear is diminished.

The dependence of this tissue/organ to maintain homeostatic control of other organ systems then diminishes, leading to ‘systems failure’. In addition, if the stem cells in the pool have been exposed to agents that prevent the normal terminal differentiation of that cell, but whereby these ‘initiated’ stem cells can be expanded in any tissue, clones of partially differentiated and non-functional appear in the tissue. This diminishes the efficacy of that tissue to function properly and, thereby, also contributes to ‘system failure’ by contributing to the breakdown of homeostatic organ system control. One clear example, that of carcinogenesis, illustrates this point.


(my coloration) LL/ I edited paragraph structure not content [B)] I hope it helps

[kevin]

EE) - Comment on Goldsmith article supporting programmed aging enhancing species fitness

Ocsrazor,

My understanding of Goldsmith's basic argument is that aging is an adaptation that promotes the fitness of the species, at the expense of the fitness of the adult individual, by enhancing evolution and genetic diversity, by ensuring that there is a turnover in the population.

From this it seems to make sense that aging and death are desirable from a species perspective and would be subject to genetic control that is linked with protecting the young, sexual maturation, and reproduction.

Would not an effect of programmed aging for the above reason, be control of reproductive fitness? I'm not sure what you mean about him confusing the two.

Although I think it is likely that senescence has genetic controls, I think that the death of an individual is a combination of damage and program in a kind of one two punch. It may be that with all the genetic controls that increase senescence turned off that we would still accumulate damage that would eventually cause systems to fail and death. I think it is possible for the two theories to coexist and in fact be linked.

Edited by kperrott, 17 March 2003 - 05:37 AM.

[ocsrazor]

EE) Weismann Aging Theory in the Goldsmith Article
Kevin-
This is literally the oldest one in the (aging research) book As I believe Goldsmith points out this was first proposed by Weisman in the late 1800's. There is a major flaw in the logic of suggesting that aging is an adapative mechanism to remove older members of the population. The logic is circular - If an organism wears out from damage it is unlikely to be able to compete with younger members of the species, so no program for senescence is necessary, the decay is part of the system. Also, older organisms with high genetic fitness would still be more desirable for a population than less fit younger ones.

I think the proper way to think of aging is as an arc, that is why I use the word trajectory fairly often. With all the molecular data we have to date it seems as if biological systems that age are set up to hit a certain peak of reproductive fitness at a particular age. What happens beyond that peak is of no concern to evolution, unless it impacts negatively on species fitness, and is just rolling down a hill. If Weisman had been right there would be a sudden onset of senescence after reproductive age - which there is not. Goldsmith appears to have confused the processes that set the arc's trajectory with the decay processes that define the downturn in the trajectory.

There is a possibility that program and damage theories could be linked, but to date there is no evidence that any aspect of aging is programmed. The one exception to this was brought up by Lazarus Long earlier, and that is unique in the animal kingdom to humans. Menopause represents a sudden change in the hormonal/metabolic program of a woman. See the earlier posts to the ideas behind why this might be true.

Best,
Ocsrazor

[kevin]

EE) Weismann Aging Theory in Goldsmith Article

Coming from 1890, the theory is extremely long lived . The difficulty damage accumulation theories have in explaining the the 'evolution like' characteristics, such as widely different lifespans in even closely related species, is responsible for why it has hung around so long even as data supporting damage accumulation has grown.

Goldsmith acknowledges the major problems of the Weissman theory one of which is :

1) Is it really feasible for a species fitness characteristic (or species level group selection characteristic) having a negative effect on individual fitness to evolve?  Some critics felt that the mechanics of evolution would preclude this.  Wouldn't an individually adverse characteristic "select out" on a time scale that was short compared to the time required for a species characteristic to "select in"?  Wouldn't an even very minor individual fitness disadvantage override an even major species advantage?

Similar to the reproductive restrictions on breeding, such as puberty, gestation or mating rituals, I think that programmed senescence may be just another mechanism to enhance the reproductive fitness of the species, making sure that sexually mature adults, have an innate ongoing biological challenge. Taking this together with the fact that it helps to increase the rate of evolution and promotes genetic diversity, it is an important component to the life cycle and a trait which is allowed to propagate.

The absence of data supporting 'programmed senescence' does not mean it doesn't exist. The only experimental evidence that I could find that might support a 'programmed senescence' theory is Kenyon's. A mechanism whereby the reproductive somatic gonad tissue sends out a signal that affects longevity in the adult, seems exactly like a 'program' which decreases the individuals fitness while enhancing turnover. As the signals require the participation of an insulin like growth receptor it is highly likely that they are affected by available energy as well and might explain the longevity effects of calorie restriction.

From Kenyon's data and the accumulating evidence supporting damage accumulation theories, I would suggest that both play a role in aging with accumulation of damage having the last say. Of course a lot more work will need to be done before the existence of a 'program' can be declared. My look at her more recent papers than Jan 2002 does not indicate that she has pursued this course, at least publicly. As their are homologues for the various proteins she studied in homo sapiens, you might expect her results to warrant some scrutiny.

--------------------------------------------------
GG) General comment on the involvement of Forkhead transcription factors in longevity.
The FoxM1B (forkhead box M1B) gene involved in mitosis and healthy cellular turnover as well as the DAF16 product, involved in promoting longevity associated with mutations in energy utilization in C. Elegans, are both forkhead transcription factors. It was pointed out by both Kenyon and Costas in their respective papers that the forkhead genes seem to play a significant role in aging. I wonder if this association is limited to the forkhead genes or if there is a broader association of longevity genes across the genome. Could the expression of the FoxM1B gene be regulated by the 'signal' sent out by 'programmed senescence', assuming that it exists.


Kev

Edited by kperrott, 18 March 2003 - 02:52 PM.

[kevin]

GG) General Comment - Article by Leonid and Natalia Gavrilov - Evolutionary Theories of Aging and Longevity

A really good overview and commentary on the evolution of aging theories:

http://www.spc.uchic...1/Evolution.htm

A specific reference to Kenyons' work with DAF2 mutant worms (but not the germline signal work that came later) from 2002 is made:

Recent discoveries of lifespan-extending mutations are spectacular. A single-gene mutation (daf-2) more than doubles the lifespan of nematodes, keeping them active, fully fertile (contrary to predictions of the disposable soma theory), and having normal metabolic rates[99].

he goes on to say:

Now, when the single-gene life-extending mutations have been found, evolutionary biologists are presented with the task of reconciling these new discoveries with the evolutionary theory of aging, and no doubt they will ultimately succeed.

Edited by kperrott, 18 March 2003 - 05:14 AM.

[kevin]

GG) General Comment on Aging and Male Fertility

The article below highlights new information regarding the gradual decline in male fertility as opposed to the more sharper onset in females. Even healthy younger individuals in their early 20's have surprisingly highg numbers of sperm with decreased motility with the passage of time. My question is what is the origin of the decrease in motility in these younger individuals that are supposedly in their prime and showing no other outward signs of aging? Is it due to damage accumulation? Are reproductive cells more sensitive than other tissues to damage? Could the signals of the germline stem cells that Kenyon refers to have some effect on the male gametes?

The bolding is mine.

---------------------------------------------------------------------------------
Feb 2003

New study of healthy men finds semen quality decreases with age

Berkeley - With each passing year, semen quality in adult men declines, suggesting that age plays a greater role in male fertility rates than previously thought, according to a new study by researchers at the University of California, Berkeley, and Lawrence Livermore National Laboratory.
The study, published Thursday, Feb. 6, in the journal Human Reproduction, suggests that even healthy men may become progressively less fertile as time goes by.

"Prior studies on semen quality typically included men who came to fertility clinics," said Brenda Eskenazi, professor of epidemiology and maternal and child health at UC Berkeley's School of Public Health, and co-author of the study. "This is one of the first studies to focus on men with no known fertility concerns, giving us a better sense of whether age affects semen quality in a healthy population."

The researchers recruited 97 men between the ages of 22 and 80 who were employed or retired from Lawrence Livermore National Laboratory. Samples were brought to the onsite research laboratory within two hours after collection to accurately measure sperm motility - its liveliness and direction of movement - and other indicators of semen quality. The researchers gathered extensive medical, lifestyle and occupational exposure history from the men, and excluded those who had smoked in the prior six months or had other relevant health problems.

While age had an effect on semen volume, the more significant impact was on sperm motility, which researchers found decreased by 0.7 percent per year. That means the chance of sperm motility being clinically abnormal is 25 percent at age 22, 40 percent by age 30, 60 percent by age 40 and 85 percent by age 60.

"Simply put, sperm slow down with age," said study co-author Andrew Wyrobek, head of the Health Effects Genetics Division at Lawrence Livermore National Laboratory. "In addition, age impacts progressive motility, which is the ability of sperm to move forward with a clear goal in mind. Sperm that swim around in circles may get trapped in the female mucosa, while sperm that moves in a linear direction will have a greater chance of colliding with the egg."

Progressive motility started to decrease in men in their 20s by 3.1 percent per year. By age 30, the probability of progressive motility being clinically abnormal is about 50 percent, gradually increasing to 82 percent by age 80.

Unlike the female biological clock - which reflects a marked decline in fertility in a woman's mid-30s - the male clock proceeds gradually, the researchers found.

The decreased fertility associated with maternal age has been well established, but understanding the effects of paternal age has become increasingly important. Over the decades, more and more men are having children at older ages. Since 1980, there has been a 24 percent increase in men aged 35 to 54 fathering children.

But research has also indicated that older men take longer to conceive than their younger counterparts. One study of 8,515 planned pregnancies found that men older than 35 have half the chance of fathering a child within 12 months compared with men younger than 25, even when the age of the mother is considered.

The study by UC Berkeley and Lawrence Livermore helps shed light on why paternal age matters.

"Women tend to be the focus in fertility issues," said Eskenazi. "What we are saying is that men are not scot-free in this. Many of us have heard of men in their 70s and older who have kids, but the probability of that happening may be lower than we thought."

The authors said that changes in semen quality with age may be due to various physiological factors, including age-related narrowing and sclerosis of the testicular tube, degeneration of germ cells, and normal changes in the prostate, or to increased probability of exposure to disease or environmental agents.
"We considered time worked at Lawrence Livermore and occupational exposure in our study, and found no evidence that they affected semen quality," said Eskenazi.

The authors note that semen quality is considered a proxy for fertility, indicating that men who wait until they are older to have children are risking difficulties conceiving.

"Of course, age is just one of many factors to consider when having a child," said Wyrobek. "We want couples to be informed when making their decision."


###
Other co-authors of the study are Sharon Kidd, Lee Moore and Suzanne Young from UC Berkeley's School of Public Health; and Eddie Sloter and Dan Moore from the Biology and Biotechnology Research Program at Lawrence Livermore National Laboratory.

The study was funded by a grant from the National Institute of Environmental Health Sciences, part of the National Institutes of Health.

Edited by kperrott, 18 March 2003 - 04:30 PM.

[kevin]

GG) General Comment on Aging - Telomeres Revisited

Although we know that telomeres get shorter with age, there has been no study to show that telomere length can predict longevity in an individual. It is generally thought that telomere shortening is a protective mechanism instead of a 'death program'. However, from the article below, research has shown there to be a direct link between shortening telomere length and age-related illness.

The article below was released Jan 30, 2003.

---------------------------------------------------------
Contact: Joe Santangelo
j.santangelo@elsevier.com
212-633-3810
Lancet

Chromosome assessment could predict increased risk of death from age-related disease

US authors of a research letter in this week's issue of THE LANCET highlight how the measurement of the ends of chromosomes in older people could give an indication of their relative risks of dying from age-related diseases.

The ends of chromosomes (telomeres) shorten with age, and this shortening may contribute to the increased risk of disease and death seen in old age; in the genetic disorder dyskeratosis congenita, for example, telomere shortening is accelerated, and patients have premature onset of many age-related diseases and early death. In the general population, however, whether people with longer telomeres live longer than those with shorter telomeres has not been tested before now.

Richard M Cawthon from the University of Utah, Salt Lake City, USA, and colleagues studied 143 individuals over the age of 60 years. When the study population were matched by age, and ranked by telomere length (done by blood assessment), those in the top half for telomere length lived four to five years longer than those in the bottom half. People with shorter telomeres were found to have higher mortality rates associated with a threefold increase in risk of death from heart disease for those in the bottom half of telomere length, and over an eightfold increased risk of death from infectious diseases for people in the bottom quartile of telomere length.

Richard Cawthon comments: "This is the first research study showing that telomere length is predictive of survival in humans. It supports the hypothesis that telomere shortening is a fundamental process of ageing, contributing to mortality from multiple age-related diseases. If this is correct, then it may be possible to extend the duration of healthy adult life using medical interventions that maintain telomere length."


###
Contact: Dr Richard M Cawthon, Department of Human Genetics, University of Utah, 15 N 2030 E Street, Room 2100, Salt Lake City, UT 84112, USA; T) 801-585-5520, F) 801-581-7796, E) rcawthon@genetics.utah.edu

Edited by kperrott, 18 March 2003 - 04:16 PM.

[kevin]

FF) Comment on Damage Theory with Reference to Male Fertility

Here is a link to an article describing a study that illustrates how paternal age relates to disease-causing mutations in sperm. Interestingly the disorders from mutated sperm increase rapidly at a paternal age similar to that of the age when maternal risk increases, age 33-35. This might imply some common vulnerability in both male and female reproductive systems to 'damage' that may have a 'timing' element. It is defintely evidence for a male 'biological clock' similar in nature to that we have touched upon before in females. The fact that the vulnerability between the sexes is timed so close together leads me to wonder what genetic components might be acting as it doesn't seem to be 'random damage' and has elements of a 'program' of sorts.

Disease-causing genetic mutations in sperm increase with men's age

Edited by kperrott, 18 March 2003 - 04:40 PM.

[ocsrazor]

Hi Kevin

EE) Follow up on Weismann and programmed aging

Weismann's ideas have been completely debunked - his logic is fatally flawed, so his ideas haven't really hung around.

One of the major problems with ideas of programmed aging is that it simply isn't necessary to explain everything we know about aging in biological organisms. If turnover of organisms is beneficial to species adaptation, mother nature doesn't need to create a mechanism to enhance aging and death, the process of decay is fundamentally part of any dissipative system. So by Ockham's Razor (sorry, couldn't resist ) most of the ideas in programmed aging create a unnecessary level of complexity in the theories of aging.

GG) Forkhead
The likely explanation of the effects of this gene family is that loss of proper control signals to transcription factors results in inappropriate gene expression causing a downstream cascade of errors. There is a significant body of literature to support these ideas - I'll find some reviews - but I probably won't be able to get to this till this weekend.

GG)Male Fertility
In general, germ cells are more resistant to damage than somatic cells, but the protective mechanisms of all systems in aging organisms decay with age. The use of the word clock in the health study article was completely inappropriate, a gradual decline is not a clock.

There really isn't a timing mechanism in loss of fertility, at least I have never seen any study suggest that there is a sudden onset of damage to germ line cells. The Glaser study is no exception. The similarity of loss of function in males and females is much easier to explain by decay mechanisms than by a clock.

GG) Telomere Health Study
I believe we covered that article elsewhere in the forums. It is very supportive of the idea of telomere's as a protective mechanism and offers no evidence that they should be part of a death prgram. There are some studies showing the correlation of telomere length and aging, but I will have to dig them out. In general, in humans their importance will be hard to define because we expose ourselves to such widely varying conditions and because they are likely a protective mechanism, different cell types will show very different rates of telomere shortening. It would take a HUGE clinical study to really answer this effectively in humans. All the data seems to be pointing to the fact that telomeres are protective, but the enzymes that regenerate them are turned off in an effort by complex organisms to stave off cancer, not as an aging mechanism.

Best,
Ocsrazor

[kevin]

Thanks for your informed opinions and any info OcsRazor... appreciate it. I've only been looking at aging theories very recently and could use them.

I've been thinking about what I've read about CR and it's effects.. and I'd be interested in any comments on what I've come up with.

FF) Comment on Both Damage and Program Theory - Caloric/Dietary Restriction

There is a good number of papers describing the benfits of calorie restriction. Decrease in free radical production, decreasing oxidative stress, ehanced immune system, protein turnover and DNA repair have been recently documented. These effects definitely have bearing on the increase in longevity of animals under CR.

The study in the link below, states like others, that the decrease in free radical production is a result of increasing the transcription of free radical scavengers while the level of mitochondrial ATP production remains the same while under CR. This result is held up by other studies which show that after a brief dip in metabolic rate, levels return to normal in CR animals. If the mechanism by which free radical production is diminished is by increased transcription of scavengers, it is under genetic control, as well it is unlikely that the upregulation of repair mechanisms is due only to an absence of free radicals and must also be under some kind of control that senses the available energy in the environment.

It has been noted that the benefits of CR occur most strongly in individuals who have not been subjected to sudden drastic drop in available calories but are most visible in animals who have had a more gradual decline in feeding.

Effects of caloric restriction on mitochondrial function and gene transcripts in rat muscle.

If the decreased male/female fertility (reproductive fitness) that occurs even in younger organisms (as observed in a previous post) is due to damage, and there exists an alternative "high transcript free radical scavenging" pathway available to the organism, why wouldn't evolution have selected for individuals who have this pathway turned on constitutively? What would be the downside to upregulated scavenging other than allocation of resources? Is there some toxic side effect that reduces viability? I haven't been able to find anything that indicates it might be.

In a CR environment the available energy to an individual is lowered. Why not just lower the metabolism and go into hibernation to wait for better times like other organisms. Might CR be a species adaptation to lowered resources, but not so low or long term that hibernation is necessary to avoid starvation? Maybe CR is an adaptation to a level of resources low enough to affect the viability of offspring but not the parents. But still, why upregulate scavenging? You would think it would be maximal at all times unless there was something harmful to have it so. As well the other processes of upregulated protein synthesis and turnover and enhanced DNA repair during CR are counterintuitive to a low energy environment.

Questions about the features of CR
1) What is is that they do?
2) Why are they active only in a low energy environment?

Answers
1) They help an animal get through hard times by upregulating repair (fighting damage/aging) on less calories. They downregulate reproduction because the resources are better spent on maintaining the individual in the face of reduced chances of offspring survival.
2) A low energy environment means that offspring of even superior animals will be less likely to survive and it is paramount to keep the parental DNA alive long enough to reproduce, even if it's getting a little long in the tooth, so if an animal is aging, it is in the best interests of the species to keep that animal strong enough to pass on it's DNA when times get better. This still doesn't explain why the life promoting features of CR are only visible in a low energy environment unless there was some benefit to not having them turned on.

As CR is a response to low resources, a pressure that affects entire populations at the same time, it seems likely that CR may be a species adaptation. I suggest that the anti-aging features of CR show up only in a low energy environment because aging has some benefit, obviously not to the individual, so therefore to the species, in a high energy environment. That benefit as Goldsmith referred to is enhanced rate of evolution (turnover of individuals) and genetic diversity. If a population is threatened by starvation and offspring are unlikely to survive it is in the best interests of the species to put some brakes on aging at the expense of evolution and diversity. Thus the pressure for evolution itself is why aging has not been selected out regardless of it's mechanism. Aging can be fought when the species is threatened with low resouces, but otherwise is allowed to continue with only as much interference as required to get the DNA moved into the next generation.

*****
Afterthoughts: An alternative to the above may be that the features of CR are an adaptation to fighting aging in a breeding/aging population that is faced with low resources. It is probably that evolution does not select for longevity as the individual only has to reproduce to have the DNA passed on, it doesn't have to get old, and most animals in the wild don't get to senescence before they are selected out. It would then be that aging is a natural process of life that only needs to be attenuated in low resource conditions so the animal could survive long enough to reproduce. When resources again became available the cell would then turn on the switches for reproduction and growth and aging would resume at it's regular pace.

I'm sure I've got more than a few holes... let me know where they are..

Kevin

Edited by kperrott, 19 March 2003 - 08:11 PM.

[kevin]

GG) General Comment on Aging Theories

Today in The Scientist I saw an advanced online publication concerning a biochemical pathway in yeast which leads to shorter lifespan through phosphorylation of a protein. The following quote from the paper reflects comments made already in my previous post on calorie restriction and seems to propose a mechanism that has a bearing on the features of CR effects on aging and reproduction.

An organism's lifespan is modulated by environmental conditions. When nutrients are abundant, the metabolism of many organisms shifts to growth or reproduction at the expense of longer lifespan, whereas a scarcity of nutrients reverses this shift. These correlations suggest that organisms respond to environmental changes by altering their metabolism to promote either reproduction and growth or long life. The only previously reported signaling mechanism involved in this response is the nutrient-responsive insulin/insulin-like growth factor-1 receptor pathway. Here we report another pathway that controls the length of yeast lifespan. Commitment to cell growth activates the Slt2p MAP kinase pathway, which phosphorylates the transcriptional silencing protein Sir3p, resulting in a shorter lifespan. Elimination of the Sir3p phosphorylation site at Ser275 extended lifespan by 38%. Lifespan extension occurs by a mechanism that is independent of suppressing rDNA recombination. Thus, Slt2p is an enzymatic regulator of silencing function that couples commitment to cell growth and shorter lifespan.

I'll have to read up a little on yeast aging but it seems that the Sir3p protein has a number of different phosphorylation sites and is probably acted upon by different kinases to produce different gene silencing patterns that directly affect longevity in yeast. As humans have this conserved protein, and related ones, it is likely that we have similar mechanisms for gene silencing and longevity.

Sir3p phosphorylation by the Slt2p pathway effects redistribution of silencing function and shortened lifespan

Edited by kperrott, 19 March 2003 - 04:19 AM.

[kevin]

GG) Comment on Aging Theories - Trade-offs between extended life-span and early life fitness can be conditional

An interesting twist on the belief that extended lifespan must necessarily be accompanied by decreased early-life fitness.

Conditional tradeoffs between aging and organismal performance of Indy long-lived mutant flies.

Marden JH, Rogina B, Montooth KL, Helfand SL.

Department of Biology, 208 Mueller Lab, Pennsylvania State University, University Park, PA 16802; and Department of Genetics and Developmental Biology, School of Medicine, University of Connecticut Health Center, Farmington, CT 06030.

Alterations that extend the life span of animals and yeast typically involve decreases in metabolic rate, growth, physical activity, andor early-life fecundity. This negative correlation between life span and the ability to assimilate and process energy, to move, grow, and reproduce, raises questions about the potential utility of life span extension. Tradeoffs between early-life fitness and longevity are central to theories of the evolution of aging, which suggests there is necessarily a price to be paid for reducing the rate of aging. It is not yet clear whether life span can be extended without undesirable effects on metabolism and fecundity. Here, we report that the long-lived Indy mutation in Drosophila causes a decrease in the slope of the mortality curve consistent with a slowing in the rate of aging without a concomitant reduction in resting metabolic rate, flight velocity, or age-specific fecundity under normal rearing conditions. However, Indy mutants on a decreased-calorie diet have reduced fecundity, suggesting that a tradeoff between longevity and this aspect of performance is conditional, i.e., the tradeoff can occur in a stressful environment while being absent in a more favorable environment. These results provide evidence that there do exist mechanisms, albeit conditional, that can extend life span without significant reduction in fecundity, metabolic rate, or locomotion.

Link to Abstract

Edited by kperrott, 25 March 2003 - 06:23 AM.

[kevin]

GG) Comment on Aging Theories - A steroid hormone affects longevity in in Drosophila

Steroid control of longevity in Drosophila melanogaster.

Simon AF, Shih C, Mack A, Benzer S.

Division of Biology 156-29, California Institute of Technology, 1201 California Boulevard, Pasadena, CA 91125, USA.

Ecdysone, the major steroid hormone of Drosophila melanogaster, is known for its role in development and reproduction. Flies that are heterozygous for mutations of the ecdysone receptor exhibit increases in life-span and resistance to various stresses, with no apparent deficit in fertility or activity. A mutant involved in the biosynthesis of ecdysone displays similar effects, which are suppressed by feeding ecdysone to the flies. These observations demonstrate the importance of the ecdysone hormonal pathway, a new player in regulating longevity.

Link to Abstract

I'm curious as the relationship of ecdysone to the hormonal mechanism proposed by Kenyon in C. Elegans if any.

Edited by kperrott, 25 March 2003 - 07:00 AM.

[kevin]

***caliban: I thought I would merge the thread on decreased proteolysis as a cause of aging as it bears on the damage accumulation theory, edit or strike at will. ***

This is an article about how reduced rates of proteolysis (protein breakdown) in mature non-developing adult cells contributes to the aging phenotype. Naturally occuring errors in protein synthesis produce abberant proteins normally. In younger, developing cells, these aberrant proteins are degraded by a high rate of proteolysis that is linked with high levels of protein synthesis. In older cells, where new protein synthesis is much lower, proteolysis is also much lower and the degradation of aberrant proteins is consequently not as high. It is proposed that these aberrant proteins accumulate and contribute to the aging phenotype. Thus aging may be a natural consequence of the reduced protein turnover experienced by mature cells.

Link to Article

Edited by kperrott, 01 August 2003 - 02:10 AM.

[kevin]

With respect to decreased proteolysis contributing to aging, the following article describes a study which proposes a link between the development of diabetes and Alzheimers through decreased activity of the enzyme "insulysin" which is known to degrade both insulin and the beta-amyloid plaques associated with Alzheimers.

http://www.eurekaler...s-iem050603.php

[kevin]

EE) Comment on Program Theory

A brand new study has come out in support of genetic controls involved in aging of the brain. These changes begin to occur before midlife and results show well choreographed genetic changes in cognitive ability.

"These changes were not a response to mutation or just a random breakdown of the system, but a very choreographed event, a clear-cut cluster of related genes and genetic programs that are being turned on and off," says Kentucky professor Philip Landfield, the senior author of the study. That this happens "was surprising, as was the fact that this is happening before mid-life."

Landfield says that even though his findings suggest that cognitive decline is orchestrated into your genes, the identification of how and when this decline occurs could be useful in preventing disease.

Study finds 150 genes that govern what happens as people age

[ocsrazor]

EE) Comment on Program Theory

Hi Kevin, boy do you know how to get me riled up

The Landfield article is an example of sloppy reporting and a very irresponsible statement by a senior researcher who should know better. The study was carried out in rats, not people as the title indicates. Rodent brain aging differs from that in humans by a significant margin.

There is no proof in the article for any programming and from the data it is most likely a response to damage or loss of the developmental program, not a preprogrammed event as Landfield stated in the interview. In fact, by that statement he contradicts what was written in his own research article.

In the discussion section the research article (J. Neurosci May 1, 2003, 23(9):3807) itself states:

Genomic regulation by itself does not constitute sufficient evidence that brain aging is "programmed" or evolutionarily selected. Instead, altered regulation could be a response to subtle early random damage (e.g., molecular errors, oxidative stress) or reflect pleiotropic genomic effects that are adaptively controlled until adulthood (Austad, 1999).

They have clearly showed that there is a cascade of system failures leading to cognitive decline, but they have not showed any link to a programmed event, which is EXTREMELY unlikely.

Best,
Peter