My title is taken from a well-known but less-well-authenticated quote from Max Planck: Science progresses funeral by funeral.Planck discovered the quantum principle in 1899, before the the physics world was ready for it.Eventually he was hailed as a visionary; but we can imagine his frustration when the smartest physicists in the world were refusing to consider his ideas because they were an unthinkable departure from the way they thought the world worked.Planck waited more than 20 years for his vindication.Last week, we lost Len Hayflick (1928 2024), a giant in the field of biology of aging.
As a young researcher in the 1960s, Hayflick discovered that cells in culture had a finite lifetime.They would replicate for a few hundred generations, then stop replicating.This contradicted a dogma (attributed to Alexis Carrel) that had been prevalent for more than forty years, which said that even though animals and plants have finite lifespans, their cells were, in principle, immortal.At the time of Hayflicks discovery, DNA was relatively new, and the fact that chromosomes had protective DNA tails, called telomeres, was not yet known.
Within 15 years, the full story came out: When DNA is copied during cell replication, a piece of each end is left uncopied.Related to this, the DNA includes a buffer of meaningless, repetitive DNA at each end so that no information is lost when the cell replicates.However, eventually the telomere is exhausted and if the cell were to replicate further, information in the coding DNA would indeed be lost.This could, in principle, be an existential threat to all life.
But never fear! Nature has provided a solution, in the form of an enzyme called telomerase.The curious thing is that telomerase is turned off by default, allowing the telomere to shorten, with life-threatening consequences.You remember from basic biology that there are two modes of cell replication, called mitosis and meiosis.Mitosis is just the cell splitting in half, each half growing anew Meiosis begins with the merger of two cells, followed by an unnecessarily complex sequence of divisions and recombinations.
Another word for meiosis is sex.It is a fact of biology going back to the single-celled eukaryotes (ciliates) that telomerase is switched on only during sex, but not during mitosis.What is this about? A few years ago, I created a computer model to demonstrate how this withholding of telomerase might have evolved as a way to prevent cells from the danger of unrestrained reproduction without sharing genes.Yes, evolution had to coerce cells, compelling them to have sex.
Coercion seems to be less necessary for bonobos.The evolutionary significance of telomere dynamicsMy point is that telomerase has very low metabolic cost and withholding it has very steep consequences for what is usually called fitness.Withholding telomerase, allowing cell senescence to happen after a few hundred generation, is the earliest example of programmed death, and to this day, telomere shortening is a factor in the aging and death of higher animals, including ourselves.Thus, telomere attrition is the clearest evidence that aging is not a failure of evolution but an active biological function.
Aging has been part of evolutions plan for life since before there were multi-celled plants and animals.This conclusion is rightfully an important part of Hayflicks legacy, a clear implication of his signature discovery.Young Hayflick had the temerity to defy the academic establishment and to pronounce what was at the time a radical reversal of scientific dogma.But he never embraced the obvious implication Cells die of telomere attritionTelomere attrition is readily avoidable, using an enzyme that is encoded in every eukaryotic cellTherefore, the cells do not want to avoid their date with the Grim Reaper.
Death on a schedule a programmed biological function.Hayflick espoused an entropic theory of agingProgrammed aging was part of Hayflicks legacy, but it was not part of his professed beliefs.In the last 20 years of his life, he was an active proponent of entropic theories of aging.This was not a radical but a reactionary position.Entropic theories of aging had been propounded and rejected in the 19th century.
It was clear to Darwin and later to August Weismann that physical theories could not explain aging, and that an evolutionary understanding was necessary.The Second Law of Thermodynamics states that entropy must always increase in a closed system.But living things are not closed systems.They take in free energy from food or sunlight and use it for growth, development, and repair.
They dump waste entropy into the environment, and thus they can accumulate order without defying any physical law.Machines must wear out, but not so living organisms.In the period 1952-1977, three evolutionary theories were proposed to explain aging.First was Peter Medawars theory of a selection shadow animals dont live long enough to die of old age, so natural selection has no chance to act on old animals.
Second was George Williamss theory of antagonistic pleiotropy genes selected for their enhancement of fertility early life have a corrosive effect on the metabolism over time.Third was Thomas Kirkwoods theory of the disposable soma animals must budget limited food energy between fertility functions and repair functions, and the repair is performed imperfectly.Hayflick eschewed the accepted evolutionary theories, reverting to a discredited theory from the past.Entropic theories are inherently related to information since, in physics, information is the opposite of entropy.
But biological information encoded in the DNA provides a new twist.This is not generic information such as can be provided by negentropy from the environment.Biology depends on DNA information that is specific to each individual and its species.
If DNA information is lost, it cannot be replenished no matter how much free energy comes in in the form of food.Abstract: The belief that aging is still an unsolved problem in biology is no longer true.Of the two major classes of theories, the one class that is tenable is derivative of a single common denominator that results in only one fundamental theory of aging.In order to address this complex subject, it is necessary to first define the four phenomena that characterize the finitude of life.
These phenomena are aging, the determinants of longevity, age-associated diseases, and death.There are only two fundamental ways in which age changes can occur.Aging occurs either as the result of a purposeful program driven by genes or by events that are not guided by a program but are stochastic or random, accidental events.
The weight of evidence indicates that genes do not drive the aging process but the general loss of molecular fidelity does.Potential longevity is determined by the energetics of all molecules present at and after the time of reproductive maturation.Thus, every molecule, including those that compose the machinery involved in turnover, replacement, and repair, becomes the substrate that experiences the thermodynamic instability characteristic of the aging process.
However, the determinants of the fidelity of all molecules produced before and after reproductive maturity are the determinants of longevity.This process is governed by the genome.Aging does not happen in a vacuum.
Aging must be the result of changes that occur in molecules that have existed at one time with no age changes.It is the state of these pre-existing molecules that governs longevity determination.The distinction between the aging process and age-associated disease is not only based on the molecular definition of aging described above but it is also rooted in several practical observations.
Unlike any disease, age changes (a) occur in every multicellular animal that reaches a fixed size at reproductive maturity, (b) cross virtually all species barriers, (c) occur in all members of a species only after the age of reproductive maturation, (d) occur in all animals removed from the wild and protected by humans even when that species probably has not experienced aging for thousands or even millions of years, (e) occur in virtually all animate and inanimate matter, and (f) have the same universal molecular etiology, that is, thermodynamic instability.Unlike aging, there is no disease or pathology that shares these six qualities.Because this critical distinction is poorly understood, there is a continuing belief that the resolution of age-associated diseases will advance our understanding of the fundamental aging process.
It will not.The distinction between disease and aging is also critical for establishing science policy because although policy makers understand that the funding of research on age-associated diseases is an unquestioned good, they also must understand that the resolution of age-associated diseases will not provide insights into understanding the fundamental biology of age changes.They often believe that it will and base decisions on that misunderstanding.
The impact has been to fund research on age-associated diseases at several orders of magnitude greater than what is available for research on the biology of aging.There is an almost universal belief by geriatricians and others that the greatest risk factor for all of the leading causes of death is old age.Why then are we not devoting significantly greater resources to understanding more about the greatest risk factor for every age-associated pathology by attempting to answer this fundamental questionWhat changes occur in biomolecules that lead to the manifestations of aging at higher orders of complexity and then increase vulnerability to all age-associated pathology? [Ref]We read from Lens tone that, even late in life, he perceived himself as a radical.
He was perceptive enough not to fall for the flawed tradeoff theories of Williams or Kirkwood.But right here in the abstract, he re-asserts Medawars reasonable but discredited idea that animals do not age in the wild (probably has not experienced aging for thousands or even millions of years).Evidence against this idea had been accumulated (independently) by Promislow, Ricklefs, and Bonduriansky.Also in this abstract is the self-contradictory idea that the body is perfectly capable of retaining biomolecules with perfect fidelity up to the age of sexual maturity, but these same molecules in the same body inevitably degrade beginning immediately thereafter.
This is not logical and it is also not true.Humans and other animals begin their exponential (Gompertz) increase in mortality risk before puberty, defying the theoretical prediction of Williams as cited above.)Len was a great, lifelong presence in the aging community, but he was wrong about programmed aging.In addition to the Hayflick Limit, there are other reasons we know that aging is programmed, among them:Aging in single-celled ciliates cannot be accounted for in any other way.The caloric restriction effect and other hormetic adaptations attest that the body is capable of attenuating aging when stressed, so certainly the body would have the same capability when unstressed.Semelparity offers obvious examples of programmed death.Genes that cause aging have been identified in all lab animals where we have looked for them.
Disable the gene and the worm lives longer.Len got the most important thing right: Medical research has been inexcusably focused on etiology of individual diseases cancer, cardiovascular, and dementia even as it is clear that all of these have a common underlying cause in the potentially preventable changes that our bodies undergo with age.
Publisher: Josh Mitteldorf ( Read More )
