• Log in with Facebook Log in with Twitter Log In with Google      Sign In    
  • Create Account
  LongeCity
              Advocacy & Research for Unlimited Lifespans

Aging mechanisms


  • Please log in to reply
2 replies to this topic

#1

  • Lurker
  • 1

Posted 16 May 2005 - 09:48 AM


This is a discussion from xprizenews.org forum which I thought would be of value to Immnst readers
- Prometheus



I wouldn't use the word "switch," because it suggests the discrete activation of a "program" of some sort. I think aging to be a continuous process of buildup of molecular lesions which eventually impair function enough to cause impaired function and pathology.


I completely agree with you on the process but have always been troubled by why it is that we do not observe molecular lesions and their effects before organisms reach a certain age (an effect exaggerated in certain species of bamboo and salmon). Don Spanton at Imminst.org also made an interesting observation which illustrates a similarly acute age related change in humans - menopause.

I suppose that one can still reconcile these observations with a non-programmatic system of aging, even if one considers that the underlying driver of such physiological changes is reflected in changes in the regulation of gene expression. But one is compelled to ask whether stochastic processes can account for all aging or whether it is the very alterations in gene regulation that permit stochastic processes to run their senescence-inducing course. Thus it becomes increasingly difficult (for me) to rationalize the existence of stochastic-only aging when considering the dramatic range of lifespan length and predisposition to degenerative disease within a species as well as the effect of progeroid syndromes. Clearly in such cases the process of aging is not simply due to increasing numbers of molecular lesions but a downmodulated ability of the cell to repair such lesions.

#2

  • Lurker
  • 1

Posted 16 May 2005 - 09:51 AM

Michael's response:

I wouldn't use the word "switch," because it suggests the discrete activation of a "program" of some sort. I think aging to be a continuous process of buildup of molecular lesions which eventually impair function enough to cause impaired function and pathology.

I completely agree with you on the process but have always been troubled by why it is that we do not observe molecular lesions and their effects before organisms reach a certain age

By "a certain age," do you mean the time when aging becomes visibly obvious (current "middle age") or the onset of the Gompertz function (in humans, in our teens)? Re molecular lesions, they are clearly accumulating at least from one's teens onwards; their buildup is drastically lower until then because they are being diluted through rapid organismal growth (cf most of the negligibly-senescing organisms, which continue to grow thru'out their LS). Re: mortality: like the "knee" in the survival curve (in humans, late middle age), the fact that this takes a while to show up is just a function of the exponential nature of the Gompertz function, which (I would advance) is an epiphenomenon of the molecular lesion buildup.

(an effect exaggerated in certain species of bamboo and salmon).

I am not familiar with the bamboo phenomenon to which you refer, but the sudden death of salmon is semelparity, not aging, and is the result of the nature of their reproductive cycle and consequent evolutionary pressure. It is so difficult for salmon to successfully make the journey upriver to their breeding grounds that few succeed, and it is statistically extremely unlikely that the same fish will make the trip twice, so theo organism has evolved to put absolutely all of its metabolic reserves into making it successfully the first time, even if this kills the organism (as it does):

Austad: The sequence of events leading to death are: (1) an extreme increase in circulating levels of the stress hormone cortisol [in order to mobilize resources to make the trip upstream -MR], leading to (2) degeneration of a number of glands and organs, including the stomach, liver, spleen, thymus, thyroid, gonads, pituitary, kidneys and cardiovascular system, which (3) causes death by multiple organ failure (McQuillan et al ., 2003). Experimentally, this series of events (degeneration of multiple organs leading to death) can be induced in immature fish by exogenous administration of cortisol. If I examine any moribund salmon, I can guarantee it will have dramatically elevated cortisol compared with a young salmon, as well as degeneration of multiple specific organs. (1)

As Austad goes on to point out, this highly stereotyped process is entirely distinct from the stochastic manifestation of pathology in mammalian aging:

Austad: Mice, even those that are genetically identical and are raised in identical circumstances, exhibit a wide variety of phenotypes as they age. For instance, in a cohort of C57BL/6 mice raised on a standard diet under specific pathogen-free conditions, about 10% of the population developed ulcerative dermatitis, the other 90% did not. In addition, about 40% of males developed cardiomyopathy by 1000 days of age, leaving 60% that did not (Turturro et al ., 2002). Similarly, some mice will develop cognitive deficits or tumours, others will not, and so on. Note that the key issue is not variation in length of life – even salmon vary in the age at which they spawn – but variation in the aging phenotype. [Ie, irrespective of their chronological age, salmon die by the end of their upstream journey; this is again quite distinct from the dropoff of the survival curve when animals die of aging -MR]. The point is that there is no aging phenotype as standard as the developmental phenotype which leads to a young adult. If there were, the search for ‘biomarkers’ of aging would not have been as difficult as it has proved to date.(1)

Don Spanton at Imminst.org also made an interesting observation which illustrates a similarly acute age related change in humans - menopause.

Again, menopause is not programmed. It happens because a woman runs out of viable eggs, leading to anestrus; the endocrine changes that cause the menopausal phenotype (which, to quibble, is arguably not "aging") are secondary to this. Ie, the organism hasn't "programmed" menopause: it has simply not designed a woman to live forever as a reproductive organism, on standard disposable soma/intrinsic-extrinsic mortality evolutionary logic (2) that she will likely be dead long before she reaches menopause. Evolution has not built in "programmed obsolescence," it has simply found that the extra reliability of a Lexus over a Cavalier does not justify the cost of building the former granted how often the models get "turned over" in practice. (I would be remiss if I didn't point out the "grandmother hypothesis"(3) as an alternative proposal, but that is not "programmed senescence" either: women have under it been given extra longevity past their reproductive lives by evolution in order to gain inclusive fitness via extra investment in grandchildren because of our long early developmental period, not had a reproductive "aging program" imposed on them).

I suppose that one can still reconcile these observations with a non-programmatic system of aging, even if one considers that the underlying driver of such physiological changes is reflected in changes in the regulation of gene expression. But one is compelled to ask whether stochastic processes can account for all aging or whether it is the very alterations in gene regulation that permit stochastic processes to run their senescence-inducing course.

But, again (a) this runs headlong into "programmed aging" and evolutionarytheory, and (b) the most consistently-observed age-related shifts in gene expression are precisely responses to damage, such as increased inflammatory, heat-shock, and antioxidant gene expression.(4,5) Stochastic damage appears to be far, far more parsimonious.

Consider the op cit case of age-related decay of mismatch repair: oxidative stress rises with age, which of course causes DNA damage, but also inhibits mismatch repair -- which of course increases the load of DNA damage. It's the stochastic process that's primary; evolution's capacity to respond to it is imperfect, not perverse.

Thus it becomes increasingly difficult (for me) to rationalize the existence of stochastic-only aging when considering the dramatic range of lifespan length and predisposition to degenerative disease within a species

That's actually good evidence that aging is not programmed: if it were, we'd expect it to show the close regularity of adolescent development. Instead, some get osteoarthritis, some heart disease, some cancer, some AD, all at different ages, etc etc. Predisposition to disease is either a real, deleterious mutation where a normally protective gene is just dysfunctional, as in BRAC mutations "causing" breast cancer or APP mutations in familial AD, which are quite distinct from the varieties of these diseases in terms of age of onset, risk factors, and even pathogenesis from standard age-related varieties of these diseases, or it is a lower degree of protection against a fundamentally stochastic process, or both.

as well as the effect of progeroid syndromes.

Almost anything that messes up normal gene function but takes a while to kill one will look like "premature aging;" the question is what if any relationship they bear to normal aging. Progeroid children do not demonstrate any but superficial phenotypic resemblances to a few, segmental aspects of "natural" aging: a progeroid child just before hir death does not have the same pathology as a person with the same life expectancy at advanced age. See previous comments re: aging, hammers, and mice.

Clearly in such cases the process of aging is not simply due to increasing numbers of molecular lesions but a downmodulated ability of the cell to repair such lesions.

But the question is what evidence exist for their having the same aetiology or pathology as "normal" aging.

-Michael

1: Austad SN.
Is aging programed?
Aging Cell. 2004 Oct;3(5):249-51. Review.
PMID: 15379846 [PubMed - indexed for MEDLINE]

2. Kirkwood TB, Austad SN.
Why do we age?
Nature. 2000 Nov 9;408(6809):233-8. Review.
PMID: 11089980 [PubMed - indexed for MEDLINE]

3. Hawkes K.
Grandmothers and the evolution of human longevity.
Am J Hum Biol. 2003 May-Jun;15(3):380-400. Review.
PMID: 12704714 [PubMed - indexed for MEDLINE]

4. Weindruch R, Kayo T, Lee CK, Prolla TA.
Gene expression profiling of aging using DNA microarrays.
Mech Ageing Dev. 2002 Jan;123(2-3):177-93.
PMID: 11718811 [PubMed - indexed for MEDLINE]

5. Lu T, Pan Y, Kao SY, Li C, Kohane I, Chan J, Yankner BA.
Gene regulation and DNA damage in the ageing human brain.
Nature. 2004 Jun 24;429(6994):883-91. Epub 2004 Jun 09.
PMID: 15190254 [PubMed - indexed for MEDLINE]v



Click HERE to rent this BIOSCIENCE adspot to support LongeCity (this will replace the google ad above).

#3

  • Lurker
  • 1

Posted 17 May 2005 - 01:44 PM

The hyperadrenocorticism associated death of salmon can be considered in respect to a mechanism that begins in the interrenal cells: a toxic level of increased synthesis of steroid due an increase in ribosomal DNA as observed in the increase in nucleoli density (1). This glucorticoid elevated induced cell degeneration (and resulting pathophysiology) is itself mediated by changes in gene regulation (1). These effects are not due to stochastic damage, as you have noted, rather when considered in terms of gene regulation appear to follow a distinct program. You make the point that these pathophysiologies are not aging becuase they are not manifesting in typical stochastic fashion. On this point I would beg to differ and ask you to look more specifically at the glucorticoid induced salmon pathophysiology which includes myofibrillar degeneration of the heart, extensive proliferation of endothelial cells in coronary arteries, extensive reduction of immune function and gastrointestinal atrophy. I do not have any difficulty seeing the parallels between such conditions and some of the age-related changes that occur in mammals. What is different is that the changes appear to be temporally compressed and driven by a genetic program that begins with overproduction of steroid until it reaches toxic levels. When these salmon are castrated prior to spawning the interrenal gland cannot undergo its hypertrophic changes and the fish escapes senescence and may live for as much as double the normal lifespan (1). That lifespan extension is possible as a result of testosterone modulation is known (2) but the dramatic effect of doubling lifespan as a result of castration has only been observed in salmon.

We may ask, then, what is the cause of aging in these castrated salmon that have had the rapid senescence program (induction of hyperadrenocorticism)removed? It appears to be stochastic. But what does stochastic really mean? If random damage occured in this fashion then should we not observe its effects from a single cell stage? What in fact we observe in humans, is that damage only appears to occur after puberty, or as you suggested once rapid organismal growth has ceased. Is this then not a program also? Supposing, for example, that the organism growth was not permitted to cease, but was counterbalanced by a certain rate of atrophy such that the dimensions and physiological characteristics of the organism were able to be kept stable (admittedly a phenomenal waste of energy evolutionarily speaking). Theoretically, such an organism should enjoy the same negligible rate of stochastic damage post-puberty as pre-puberty. The point, of course, is that being able to modulate a program infers that a program exists.

On bamboo: like salmon, bamboo experiences a similarly sudden and catastrophic senescence event following a single flowering cycle.



(1) 1990, p83-95
Longevity Senescence and the Genome
Finch, C

(2) Nature. 1993 Nov 18;366(6452):215.
Lifespan and testosterone.
Nieschlag E, Nieschlag S, Behre HM.

sponsored ad

  • Advert



0 user(s) are reading this topic

0 members, 0 guests, 0 anonymous users