August 03, 2003
Redundant System Failures That Lead To Death May Start Prenatally

Leonid A. Gavrilov of the University of Chicago Center on Aging has kindly sent me notice of a paper he has just published with Natalia S. Gavrilova on the importance of redundancy loss in redundant systems as a cause of aging.

Reliability Theory Explains Human Aging And Longevity

Our bodies backup systems don't prevent aging, they make it more certain. This is one offshoot of a new "reliability theory of aging and longevity" by two researchers at the Center on Aging, NORC at the University of Chicago.

The authors presented their new theory at the National Institutes of Health (NIH) conference "The Dynamic and Energetic Bases of Health and Aging" (held in Bethesda, NIH). Their theory of aging is published this month by the "Science" magazine department on aging research, Science's SAGE KE ("Science of Aging Knowledge Environment").

The authors say, "Reliability theory is a general theory about systems failure. It allows researchers to predict the age-related failure kinetics for a system of given architecture (reliability structure) and given reliability of its components."

"Reliability theory predicts that even those systems that are entirely composed of non-aging elements (with a constant failure rate) will nevertheless deteriorate (fail more often) with age, if these systems are REDUNDANT in irreplaceable elements. Aging, therefore, is a direct consequence of systems redundancy."

In their paper, "The quest for a general theory of aging and longevity" (Science's SAGE KE [Science of Aging Knowledge Environment] for 16 July 2003; Vol. 2003, No.28, 1-10. http://sageke.sciencemag.org ), Leonid Gavrilov and Natalia Gavrilova offer an explanation why people (and other biological species as well) deteriorate and die more often with age.

Interestingly, the relative differences in mortality rates across nations and gender decrease with age: Although people living in the U.S. have longer life spans on average than people living in countries with poor health and high mortality, those who achieve the oldest-old age in those countries die at rates roughly similar to the oldest-old in the U.S.

The authors explain that humans are built from the ground up, starting off with a few cells that differentiate and multiply to form the systems that keep us operating. But even at birth, the cells that make up our systems are full of faults that would kill primitive organisms lacking the redundancies that we have built in.

"It's as if we were born with our bodies already full of garbage," said Gavrilov. "Then, during our life span, we are assaulted by random destructive hits that accumulate further damage. Thus we age."

"At some point, one of those hits causes a critical system without a back-up redundancy to fail, and we die."

As the authors puts it, "Reliability theory also predicts the late-life mortality deceleration with subsequent leveling-off, as well as the late-life mortality plateaus, as inevitable consequences of REDUNDANCY EXHAUSTION at extreme old ages."

All those who have achieved the oldest-old age have very few redundancies remaining, therefore they can't accumulate many more defects: They simply die when the next random shock hits a critical system. Hence, the mortality rates tend to level off at extreme old ages, and people all over the world die at relatively similar rates on average. The initial differences in body reserves (redundancy) eventually disappear.

In the authors' words, "The theory explains why relative differences in mortality rates of compared populations (within a given species) vanish with age, and mortality convergence is observed due to the exhaustion of initial differences in redundancy levels."

This fundamental theory of aging and longevity is grounded in a predictive mathematical model that accounts for questions raised by previous models addressing the mechanisms of aging, mortality, survival and longevity.

The authors are research associates at the Center for Aging at the University of Chicago's National Opinion Research Center. Their research was sponsored by the National Institute on Aging.

Let's think about this intuitively. We have many subsystems which are each critical to our survival. Also, there is a lot more redundancy in them than it first appears. We know we have 2 lungs and 2 kidneys and can survive with only one of them. But there are many redundancies at lower levels. For instance, we also have many little air sacs in each lung and can survive if only some of them get damaged. Also, there any many nerves innervating the heart telling it to beat and if a small fraction of them die off for most people the surviving nerves can still send enough messages to keep the heart beating well. Or how about the skin? Many cells are dying all the time and we can even experience a burst of cell deaths due to a sunburn and still survive. The same redundancy at the cellular level happens in many parts of the body. Half the cells in the liver can die off for some reason and yet the liver can usually function well enough in the short term with the rest of the cells to have time to grow back the lost cells.

An example of loss of redundancy playing a role in the development of diseases of old age was the report post here recently Bone Marrow Stem Cell Aging Key In Atherosclerosis. Once the pool of replacement cells for artery repair becomes depleted we become far more susceptible to atherosclerosis. It is possible that at the start of life that people differ with regard to the total number of replacement cells that their pool of bone marrow stem cells are capable of supplying.

The Pub Med abstract and the full text of the paper (in PDF format) are available online. Also see the web site of the authors for a lot more information about their work on theoretical models of aging.

University of Cambridge biogerontologist Aubrey de Grey was kind enough to respond to my request for some comments on the signficance of this work:

This work is certainly good work in its own terms, i.e. the mathematics is novel and rigorous. Whether it implies/motivates (or the opposite) any particular approach to life extension is a bit less clear, because the discovery of a mathematical model that fits observed data doesn't tell us anything in the Popperian sense, i.e. it doesn't falsify any hypothesis. This turns out to be true for essentially all analyses of actual and hypothetical survival patterns: even with very big datasets it turns out to be rather easy to fit the observed data to within statistical non-significance with more or less any theory. Occasionally people fool themselves into thinking they have falsified one or other of the major mortality models (eg Michael Rose's paper in April's Exp Gerontol), but it tends to take about a day before the flaw in their logic is exposed (in that case by me, correspondence out any day now in August's Exp Gerontol).

However, this really means a great deal more in terms of competition between hypotheses than you might think, because of what happens if you think of the issue the other way around. What work like this can show very robustly is that hypotheses which we might have thought WERE obviously falsified by known data are in fact not falsified at all. In the case of this work, what they show is that we may in fact be shot through with "defects" - things that make us live less long than if we didn't have them - even by birth. It is very counterintuitive that this should be consistent with observed mortality patterns, i.e. almost no mortality until say 2/3 of the life expectancy and then a sharp acceleration -- certainly I would think that that implies very nearly no defects at birth. If we THEN ask what the practical upshot may be, we can come up with quite interesting answers. First off, this is extremely relevant to the rather neglected area of epigenetic influences on aging that are laid down prenatally, of which the only well-known one is the relationship between birth weight and lifespan (and the total absence of such a relationship in the case of twins -- a real first-class mystery, that one) but of which there are lots of examples surveyed in Finch and Kirkwood's "Chance, Development and Aging" of a few years ago. So it certainly highlights the importance of prenatal care and the potential relevance of identifying aspects of damage that are already present at birth.

Think about that. There are certainly people walking around (in some cases not even able to walk) with obvious diagnosed birth defects. However, if this model is correct we might all be born shot through with "defects".

One cause of the differences in life expectancy between people may be random differences in the distribution of defects. Imagine two organs A and B which are each critical to survival (could be the heart and the liver for instance). If on average we are each born with 5 defects per organ just due to random events that happen during embryonic development then some may be born with only 2 defects per organ while others may be born with 8 defects per organ. Also, one person might be born with 10 total defects with 5 in each organ while another person might be born with 2 defects in A and 8 defects in B. If each organ tends to accumulate defects at the same rate and each fails with the same total number of defects then we'd be better off born with 5 in each organ rather than 2 in one organ and 8 in another since the failure of just one critical component is enough to cause death.

Random processes are just one source of defects. Genetic inheritance, maternal diet, maternal stress, maternal exposure to toxins, and other factors contribute to how well or poorly a fetus develops.

It would be valuable to have ways to measure the amount of redundancy still existing in each person from birth on throughout life. If one had some way of knowing which of one's subsystems were most lacking in redundancy one could pursue strategies designed to minimize stresses and damage to those subsystems.

The basics of what we have to do to reverse aging remain the same. We need to be able to supply rejuvenated replacement stem cells and grow replacement organs. We need to be able to do gene therapy to deliver various forms of revitalizing genes such as replacements for damaged mitochondrial genes and also genes that code for enzymes that can break down accumulated intracellular junk. See Aubrey de Grey's longer list of potential rejuvenation therapies. See my Aging Reversal archive for more on promising approaches for reversing aging.

Share |      Randall Parker, 2003 August 03 01:56 PM  Aging Reversal


Comments
Dr. Leonid Gavrilov said at August 5, 2003 7:05 PM:

Greetings,

May I bring your attention to one more new publication on related topic.

This new book chapter presents evidence for early-life (developmental)
programming of aging and lifespan, which may be interesting to you:


"Early-Life Factors Modulating Lifespan." pp. 27-50.
In: Rattan, S.I.S (Ed.). Modulating Aging and Longevity.
Kluwer Academic Publishers, Dordrecht
Hardbound, ISBN 1-4020-1369-8
July 2003, 336 pp.
http://www.wkap.nl/prod/b/1-4020-1369-8
and
http://www.wkap.nl/prod/b/1-4020-1369-8?a=1


Kind regards,

-- Leonid Gavrilov
Author of the book "The Biology of Life Span"
http://www.src.uchicago.edu/~gavr1/index.html#Book

Dr. Leonid Gavrilov said at August 15, 2003 4:39 PM:

Greetings,

May I also bring your attention to related discussions of this aging theory, which take place at the Science Advisory Board, SAB:

http://www.scienceboard.net/

Specifically, see discussion topic "The Quest for the General Theory of Aging" at:

http://www.scienceboard.net/forum/topic.asp?TOPIC_ID=348&FORUM_ID=35&CAT_ID=12.

Kind regards,

-- Leonid Gavrilov
Senior Member of the Science Advisory Board
(http://www.scienceboard.net/)

Dr. Leonid Gavrilov said at August 19, 2003 9:22 PM:

Dear Colleagues,

This is a short note to British colleagues regarding our
forthcoming scientific visit to England this September/October, 2003
as invited speakers on our new theory of aging and
related findings

We would be delighted to use this opportunity and
to give some additional lectures at your organization too
-- just please let us know, if you are interested.

Detailed description of our studies and findings,
as well as their coverage by "Science" , "Scientist",
"Sunday Times, London" and "Encyclopedia Britannica"
is available at our scientific website:
http://www.src.uchicago.edu/~gavr1/

Kind regards,

Leonid Gavrilov, Ph. D., and Natalia Gavrilova, Ph. D.
Authors of the book "The Biology of Life Span"
http://www.src.uchicago.edu/~gavr1/index.html#Book

Dr. Leonid Gavrilov said at November 5, 2003 9:00 PM:

Greetings,

This to inform that all our earlier cited scientific publications and documents has been moved to a new website: http://longevity-science.org/

Here is a brief description of our new scientific website on longevity science at new URL: http://longevity-science.org/

Any comments and suggestions are welcome!


-- Leonid Gavrilov
--------------------------------


Website title:

Longevity Science: Unraveling the Secrets of Human Longevity & Aging


Website URL:

http://longevity-science.org/


Website Description:

This web site represents research efforts aimed to understand the mechanisms of aging and longevity in order to extend healthy and productive human lifespan


Key words:

longevity, human longevity, lifespan, life span, life extension, aging, ageing, anti-aging, anti-aging medicine, gerontology, senescence, mortality, biodemography, demography, reliability, reliability theory, season of birth, parental age, biology, human biology, theoretical biology, mutation, evolution, sex, epidemiology, longevity studies, NIA, Center on Aging, NORC, University of Chicago, population, National Institute on Aging, immortality, centenarians, biogerontology, seasonality

Dr. Leonid Gavrilov said at December 9, 2003 7:49 PM:

Greetings,

This is an update for our scientific and educational website on human longevity studies:

Website title:
Longevity Science: Unraveling the Secrets of Human Longevity & Aging

Website URL:
http://longevity-science.org/

Website Description:
This web site represents research efforts aimed to understand the mechanisms of aging and longevity in order to extend healthy and productive human lifespan

Key words:
Longevity, human longevity, lifespan, life span, life extension, aging, ageing, anti-aging, anti-aging medicine, gerontology, senescence, health, scientific news, free articles, women studies, astrology testing, scientific books, mortality, biodemography, demography, reliability, reliability theory, season of birth, parental age, biology, human biology, theoretical biology, mutation, evolution, sex, epidemiology, longevity studies, NIA, Center on Aging, NORC, University of Chicago, population, National Institute on Aging, immortality, centenarians, biogerontology, seasonality, Death or Mortality; Demography; Epidemiology; Genetics; Gerontology; Mathematical Modeling; Aging; Aging; Anti-aging; Anti-aging Medicine; Biodemography; Biodemography of Human Longevity; Biogerontology; Biology; Biology of Life Span; Centenarians; Demography; Early-life Predictors of Longevity; Epidemiology; Evolution; Evolutionary Theories; Evolutionary Theories of Aging; Genetic Epidemiology; Gerontology; Gompertz Law; Human Biology; Human Longevity; Immortality; Life Extension; Life Span; Lifespan; Longevity; Longevity Predictors; Longevity Studies; Mechanisms of Aging; Mortality; Mutations; Parental Age; Parental Age Effects; Paternal Age; Reliability; Reliability Theory; Reliability Theory of Aging; Season of Birth; Seasonal Effects; Senescence; Sex; Sex Differences; Survival; Theoretical Biology

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