ArticlePDF AvailableLiterature Review


The idea that bodies wear out with age is so ancient, so pervasive, and so deeply rooted that it affects our thought in unconscious ways. Undeniably, many aspects of aging, e.g., oxidative damage, somatic mutations, and protein cross-linkage are characterized by increased entropy in biomolecules. However, it has been a scientific consensus for more than a century that there is no physical necessity for such damage. Living systems are defined by their capacity to gather order from their environment, concentrate it, and shed entropy with their waste. Organisms in their growth phase become stronger and more robust; no physical law prohibits this progress from continuing indefinitely. Indeed, some animals and many plants are known to grow indefinitely larger and more fertile through their lives. The same conclusion is underscored by experimental findings that various insults and challenges that directly damage the body or increase the rate of wear and tear have the paradoxical effect of extending life span. Hyperactive mice live longer than controls, and worms with their antioxidant systems impaired live longer than wild type. A fundamental understanding of aging must proceed not from physics but from an evolutionary perspective: The body is being permitted to decay because systems of repair and regeneration that are perfectly adequate to build and rebuild a body of ever-increasing resilience are being held back. Regardless of the reason for this retreat, it should be more fruitful to focus on signaling to effect the ongoing activity of systems of repair and regeneration than to attempt repair of the manifold damage left in the wake of their failure.
Aging Is Not a Process of Wear and Tear
Josh Mitteldorf
The idea that bodies wear out with age is so ancient, so pervasive, and so deeply rooted that it affects our
thought in unconscious ways. Undeniably, many aspects of aging, e.g., oxidative damage, somatic mutations,
and protein cross-linkage are characterized by increased entropy in biomolecules. However, it has been a
scientific consensus for more than a century that there is no physical necessity for such damage. Living systems
are defined by their capacity to gather order from their environment, concentrate it, and shed entropy with their
waste. Organisms in their growth phase become stronger and more robust; no physical law prohibits this
progress from continuing indefinitely. Indeed, some animals and many plants are known to grow indefinitely
larger and more fertile through their lives. The same conclusion is underscored by experimental findings that
various insults and challenges that directly damage the body or increase the rate of wear and tear have the
paradoxical effect of extending life span. Hyperactive mice live longer than controls, and worms with their
antioxidant systems impaired live longer than wild type. A fundamental understanding of aging must proceed
not from physics but from an evolutionary perspective: The body is being permitted to decay because systems of
repair and regeneration that are perfectly adequate to build and rebuild a body of ever-increasing resilience are
being held back. Regardless of the reason for this retreat, it should be more fruitful to focus on signaling to effect
the ongoing activity of systems of repair and regeneration than to attempt repair of the manifold damage left in
the wake of their failure.
It is an an idea so common, so embedded in the thought
process of gerontologists and medical practitioners that it
is seldom questioned: Aging is a physical process of deteri-
oration, because damage accumulates faster than it can be
repaired. At least since the Renaissance, scientists and phi-
losophers, poets, doctors, and laymen have adopted this
understanding of aging. It remains the basis of a great deal of
medical research today, and it is at the core of the Strategies
for Engineered Negligible Senescence (SENS) program. But
despite its ubiquity and common sense appeal, this idea was
thoroughly discredited by physicists of the nineteenth cen-
tury, and their analysis remains cogent. Evolutionary bi-
ologists, who claim the high ground in understanding of
deep causes in biology, have for the last century regarded
damage as a result, not a cause of aging.
In this article, the theoretical relationship between life and
the Second Law of Thermodynamics will be clarified, and
reasons to suppose that physics requires living things to
age will be deconstructed. Some predictive failures of the
‘‘Damage Theory’’ will be catalogued. Finally, if the enor-
mous range of natural aging rates—at least six orders of
magnitude—is not sufficient reason to discredit the idea that
aging is inevitable, then certainly the existence in nature of
organisms that do not age at all must be a disproof.
History of Thermodynamics
The idea that order spontaneously and universally dis-
solves to disorder is very old, but it was not until 1850 that
this notion was codified quantitatively as the Second Law of
Thermodynamics. Clausius
is credited with incorporating
entropy as a quantitative physical variable. He distinguished
ideal ‘‘reversible’’ processes from the ‘‘irreversible’’ processes
that take place in the real world and demonstrated that ideal
processes conserve entropy, whereas in realistic cases, en-
tropy must always increase. The Second Law of Thermo-
dynamics is sometimes stated thus: In any closed physical
system, the entropy will increase, until it attains its maxi-
mum value. The state of the system in which entropy realizes
its maximum value is called ‘‘equilibrium.’
The Second Law explains why a rock tumbles down a hill,
turning its potential energy of gravitation into low-grade
heat. Metal fatigue and oxidation are familiar examples of
irreversible processes in which entropy accumulates. But the
Department of Ecology and Evolutionary Biology, University of Arizona, Tucson, Arizona.
Volume 13, Number 2-3, 2010
ªMary Ann Liebert, Inc.
DOI: 10.1089=rej.2009.0967
law applies only to closed (isolated) systems, and it is pos-
sible for processes to accumulate information in one object,
while entropy is dispersed elsewhere. For example: As a pool
of water evaporates, the liquid can cool (lower entropy) be-
cause the gas disperses with higher entropy that more than
compensates. If there is salt in the water, the salt may congeal
into a crystal as the water disappears. The crystal has much
lower entropy than the dissolved species. It is the water
vapor that carries the higher entropy. The disequilibrium
between the liquid water and warm, dry air above it was
sufficient to drive the process and create the crystal in its
highly ordered state.
Living things have taken this loophole in the Second Law
and developed it as a specialty. The ongoing ability to gather
free energy from the environment and concentrate it as order
within, while discarding entropy as waste is a defining
property of living systems. Every multicellular organism is
capable of growing from seed into a fertile adult. Typically,
the mortality risk of the adult is lower than the immature
stage, and certainly the fertility is (by definition) higher. So
growth and development constitute ‘‘negative aging’’ in both
the biological and the thermodynamic senses. There is no
theoretical reason this process could not continue indefi-
nitely. The organism could continue to grow larger, more
fertile, and more resistant to mortality of all sorts after it
attained maturity, and some, in fact, do just this.
For an
explanation of senescence, we should appeal to evolutionary
theory, not to thermodynamics.
Weismann’s Role
If living organisms wore out like machines, there would
be no need for an evolutionary account of aging. But mul-
ticellular life succeeds in the remarkable feat of constructing
a complex system from fragments found in the environment,
using only a genetic blueprint, only to fail at the seemingly
much more modest task of maintaining the completed soma
in reasonable working order. In the generation after Charles
Darwin, August Weismann articulated the essential biolog-
ical conundrum of aging and sought an explanation not from
physics but from evolution. Weismann is credited with the
first evolutionary theory of aging, but his departure from
physical wear and tear was not so clean. His original theory
was based on a presumption that damage to the adult soma
was unavoidable and that damage must accumulate over
Weismann backed away from this theory later in his life
and wrote instead of the loss of immortality in somatic cells,
as it became an unnecessary luxury. But it was not until Peter
Medawar that the essential logical flaw in Weismann’s
original hypothesis was articulated: ‘‘Weismann assumes
that the elders of his race are worn out and decrepit—
the very state of affairs whose origin he purports to be
inferring—and then proceeds to argue that because these
dotard animals are taking the place of the sound ones, so
therefore the sound ones must by natural selection dispos-
sess the old.’’
Medawar realized full well that there is no thermody-
namic necessity for wear and damage to accumulate. He
sought not a physical explanation for aging, but an evolu-
tionary explanation, grounded in the declining force of nat-
ural selection with age. The evolutionary community has not
looked back, and today there is broad agreement that aging
cannot be explained as a physical necessity, but must be
understood like every other biological phenomenon in terms
of natural selection.
Is Somatic Repair a Difficult or Expensive Process?
It has been argued (most famously by W.D. Hamilton)
that repair of the adult organism cannot be perfect, and that
errors in repair and maintenance must inevitably accumu-
late, leading eventually to the organism’s demise. This is also
a premise of the Disposable Soma theory of T.B. Kirkwood.
But the reasoning is logically flawed, as James W. Vaupel
has demonstrated. There is nothing perfect about a freshly
minted adult, and the maintenance of that adult is not a
process that demands perfection. For example, when a bone
is broken, it knits back together in a few weeks’ time. The
bone was not perfect before it was broken, and it is not
perfect after it heals. But mended bones are stronger than the
original and will not break again in the same place. Bone
repair may be said to be better than 100% efficient and
clearly requires a finite amount of free energy.
The mammalian body is equipped with an impressive
array of repair mechanisms, from the molecular level up to
the tissue level. Proteins are recycled into constituent amino
acids when they become damaged; it is only in aged animals
that the this process becomes inefficient.
DNA is constantly
monitored and repaired. Underperforming mitochondria are
eliminated and replaced under control of the cell nucleus.
And whole cells are routinely destroyed via apoptosis and
replaced when they become damaged.
All of these pro-
cesses are adequate in youth to maintain the organism
without loss of function, and they fail progressively as a
result of aging, causing aging damage to accumulate. But
their efficiency in youth attests to the fact that repair can be
as efficient as it needs to be.
Loose analogies may suggest that at some point in the life
of an organism, damage accumulates to the point where
repair of the organism is energetically less costly than re-
placement through reproduction. This idea is implicit in the
foundation of the Disposable Soma theory.
Our expe-
rience with man-made appliances lends credibility to the
idea; but many of the reasons that a 10-year-old car can be
replaced more cheaply than it can be repaired do not have
analogs in the world of biology. Autos must be dismantled
before they can be repaired and reassembled afterward,
whereas biological organisms repair themselves from the
inside out. Auto manufacturers price the new car with a low
profit margin, and overcharge for replacement parts, because
the customer has nowhere else to go. Auto repair is pur-
chased at market rates for European or American labor,
while cheap Asian labor and cheaper robots are used by
factories in which the autos originate. Thus, we should not
expect our intuitions about automobiles to apply to living
The energetic cost of repairing an aging soma is substan-
tially less than the the total energetic cost of reproducing one
new adult. Repairing DNA and stringing together amino
acids are both processes with low intrinsic theromodynamic
costs and both have been highly optimized for energy effi-
ciency. In contrast, the cost of anabolism is quite substantial,
and the cost of reproduction is magnified by high mortality
rates of the immature. For example, a female mouse con-
sumes twice as much food energy while pregnant and lac-
All of this suggests that an enormous quantity of
resource has been consumed to create a single mature adult,
and evolutionary pressure to protect and preserve that in-
vestment ought to be correspondingly high.
A few mammals and many lower animals are capable of
regenerating whole body parts after dismemberment. Ellen
has shown that this capability is latent in
mice as well and can be switched back on with a simple
blood factor. Almost all plants and many animals can re-
generate. The process is expensive relative to repair, but
cheap compared to the full cost of reproducing a new adult
individual. Starfish have a legendary capacity for regenera-
tion, and half a starfish can readily grow back its other half.
And yet, starfish have a life expectancy of about 8 years. If a
limb is severed from a 6-year-old starfish, it regenerates a full
animal that remembers its age, so that it has 2 years re-
maining in its life expectancy. The persistence of senescence,
even in the presence of extensive regenerative capacity, poses
a conundrum: How is the memory of the starfish’s age car-
ried into the young, regenerated tissue?
Tooth wear is an example of true damage accumulation
leading to senescence of the elephant. Elephants can grow six
full sets of teeth in a lifetime, but if they should outlive their
last set of teeth (and some have been found in nature to do
so), they will become toothless and must starve to death. It is
a strange wear-and-tear theory that can explain how it is that
the elephant’s capacity for regeneration ends after its sixth
set of teeth.
Theories of Oxidative Damage
It is over 50 years since Denham Harman
first proposed
that aging is caused by progressive damage to the body’s
chemistry from the reactive oxygen species (ROS), which are
an inescapable byproduct of respiration. The theory has in-
spired thousands of research projects and continues to have
great currency today. The ongoing attraction of the theory is
that there is broad evidence that oxidative damage to key
proteins accompanies aging. Extensive experimentation has
explored the use of antioxidants as an antiaging intervention,
both in the laboratory and in human epidemiology. The re-
sults of these studies have been disappointing, with the
largest studies actually showing increased mortality for
subjects ingesting antioxidants.
The emerging picture of the
relationship between oxidation and aging is complex: Per-
oxide is an important signal in the pathways connected to
Apoptosis has two faces: It is both an essential
mechanism for cleansing the body of infected, cancerous,
and damaged cells, and is also implicated in the wasting of
and the loss of brain cells in Alzheimer
and Parkinson diseases.
The body’s important antioxi-
dants are expressed at lower levels with age, which both
accounts for the observed increase in oxidative damage
and suggests that oxidative damage is secondary effect
rather than a root cause of aging.
Theories of oxidative damage are elegant and attractive,
but some of the experimental results seem almost to mock
the predictions of the theory. Physical activity generates co-
pious free radicals, and yet high levels of physical activity are
generally associated with longer, not shorter average life
spans. Hanson and Hakimi
report on a genetically modi-
fied mouse that has extra mitochondria. These mice are
phenomenally active, eat much more than wild-type mice,
and burn it all up, yet they live almost 2 years longer than
wild-type mice and remain reproductively active 2 years
longer. Two of the body’s most essential antioxidants are
superoxide dismutase (SOD) and unbiquinone. Mice in
which one copy of the gene for SOD has been knocked out
have half as much SOD in their tissues, and measurements of
oxidative damage to DNA show that it is far higher than
controls; yet the heterozygous Sod2
mice lived slightly
longer than controls.
SOD knockout worms also have ex-
tended lifespan, coupled with enhanced markers of oxidative
clk-1 is a gene originally discovered in worms,
activation of which increases life span by an average 40%.
The homologous gene in mice is mclk1, and its deletion also
leads to enhanced life span.
Only later was it discovered
that the action of clk-1 is essential for synthesis of ubiqui-
none, and, as a result, clk-1 mutants are less able to quench
the ROS products of mitochondrial metabolism—yet they
live longer.
The first data were reported for heterozygous
worms, and it was thought that the homozygous
=mutant was not viable. More careful experimentation
revealed that the =worm developed on a delayed
schedule, and subsequently lived to a record ten times the
normal Caenorhabditis elegans life span.
This worm has no
capacity to synthesize ubiquinone, and its prodigious life
span is truly a paradox from the perspective of the damage
theories of aging.
Naked mole rats live eight times longer than mice of
comparable size, though the latter seem to be better pro-
tected against oxidative damage.
And life spans of mice
are generally a few years, while bats live for decades, despite
a higher metabolic rate and greater load of mitochondrial
The laboratory of Arlan Richardson at the Barshop In-
stitute of the University of Texas reports on the results of an
8-year, systematic study of a wide variety of genes coding for
antioxidant enzymes. For each target gene, they studied both
knockout mice and mice with extra copies of the gene, and
assayed life spans under standard conditions. The only in-
tervention that affected life span was the sod1 gene. They
published their study under the provocative title, ‘‘Is the
oxidative stress theory of aging dead?’’
Circling for the
wounded beast, LaPointe and Hekimi draw a parallel con-
clusion from their own experiments in an article titled,
‘‘When an aging theory ages badly.’
It is certainly true that much of the damage we associate
with senescence can be traced back to oxidative damage
from ROS created as a byproduct of mitochondrial processes;
but biochemical protections could be adequate to protect
against these hazards with essentially perfect efficiency.
Disposable Soma Theory
Kirkwood’s Disposable Soma theory is the only main-
stream evolutionary theory that connects to the idea of ac-
cumulated damage. The thrust of Kirkwood’s idea is that
damage accumulates because the body must budget caloric
energy and skimps on repair to enhance reproduction in a
compromise that optimizes net reproductive fitness. The
biggest problem with the Disposable Soma theory is what it
predicts about the relationship between food energy and
aging. If aging were primarily a matter of insufficient food
energy to both reproduce and repair, then more food energy
would lessen the need for compromise, and the body should
be able to both live longer and increase fertility. The caloric
restriction effect is the oldest, most robust, and best-known
intervention to increase life span, and it is absolutely irrec-
oncilable with the Disposable Soma theory.
It is also a robust prediction of the Disposable Soma theory
that life span should be shortened by the energetically ex-
pensive act of reproduction. In animals, there is no evidence
that this is the case,
and in humans, there seems to be a
small positive correlation between fertility and life span.
Presenescence, Negligible Senescence, Negative
Senescence, and Postsenescence
If aging were a process of stochastic damage, then that
damage would be accumulating inexorably, regardless of
species, of environment, or time of life. The many examples
of nonaging in nature demonstrate that aging is not a
physical necessity. All multicellular life is capable of building
itself up from seed. During the process of growth, aging is
typically absent. In fact, if aging is defined demographically
as increasing mortality rates along with decreasing fecun-
dity, then the early period of growth is a time of negative
Semelparous animals from mayflies to octopi may be
distinguished as a subcategory of animals that suffer no (or
negative) actuarial senescence before they die precipitous-
Many plants and some animals do not age measurably
over hundreds of years.
Vaupel has collected examples of
animals that enjoy negative senescence, including coral, sea
urchins, some mollusks and desert lizards.
Fahy offers un-
ique details and adds many more examples, including car-
tilaginous fish and turtles.
The phenomenon of late life mortality plateaus was not
predicted by any of the evolutionary theories of aging and
certainly not by wear-and-tear theories. It was discovered in
the 1990s that in Drosophila,C. elegans, and humans mortality
rates cease their exponential growth and level off late in life.
(These are the only three animal species for which suffi-
ciently large samples have been studied to detect this phe-
nomenon.) The phenomenon is difficult to reconcile with
damage theories of aging. It must be considered paradoxical
that damage should cease its relentless advance at a point in
the life cycle when repair mechanisms are at their weakest.
If Not Damage, What Then?
The thesis of this work has been negative: Aging of living
organisms is essentially different from the process of accu-
mulated damage that causes inanimate machines to wear out
over time. If aging cannot be explained as a process of ac-
cumulated damage, what then is its cause? The answer must
be sought in the evolutionary process that created life. Be-
cause the aging phenomenon is so ubiquitous in the bio-
sphere, and because genes that cause aging are related over
widely separated taxa, it makes sense to seek a unified an-
swer to the question of why organisms age.
But the phenomenology of aging is diverse and often
paradoxical, refusing to be tamed by simple, unifying hy-
potheses. The community of evolutionary theorists has no
consensus about the ultimate provenance of aging; instead,
there are competing theories, with the best-accepted ones all
deriving from Medawar’s original insight about the declin-
ing force of natural selection.
It may be that the paradoxical
phenomenology, including results cited herein, is inconsis-
tent with prevailing notions of individual fitness, and that
evolutionary theory will have to stretch to accommodate the
Fortunately, there is a clear message for antiaging research
that does not depend on which evolutionary theory is fa-
vored. The message is that aging is under the body’s control.
If there is no physical necessity for damage to accumulate,
there is also no necessity for bioengineers to invent elaborate
solutions for repairing that damage. It should be far easier to
reprogram the body’s signaling apparatus, turning on
mechanisms that are perfectly capable of maintaining the
body in a state of youthful vigor.
1. Clausius R. On the motive power of heat and the laws which
can be deduced from it for a the theory of heat. Annalen der
Physik und Chemie 1850;79:500–524.
2. Clausius R. On a modified form of the second fundamental
theorem in the mechanical theory of heat. In: The Mechan-
ical Theory of Heat, Hirst TA. ed. van Voorst, 1867:111–135.
3. Vaupel JW, et al. The case for negative senescence. Theor
Popul Biol 2004;65:339–351.
4. Weismann A, et al. Essays upon Heredity and Kindred Bio-
logical Problems, 2nd ed. Clarendon Press, Oxford,1891, 2 v.
5. Medawar PB. An Unsolved Problem of Biology: An inau-
gural lecture delivered at University College, London, 6
December, 1951. H. K. Lewis and Company, London, 1952,
24 pp.
6. Hamilton WD. The moulding of senescence by natural
selection. J Theor Biol 1966;12:12–45.
7. Kirkwood T. Evolution of aging. Nature1977;270:301–304.
8. Knight JA. The biochemistry of aging. Adv Clin Chem
9. Yoneda M, et al. Marked replicative advantage of human
mtDNA carrying a point mutation that causes the MELAS
encephalomyopathy. Proc Natl Acad Sci USA 199;89:11164–
10. Izyumov DS, et al. ‘‘Wages of fear’’: transient threefold de-
crease in intracellular ATP level imposes apoptosis. Biochim
Biophys Acta 2004;1658:141–147.
11. Carranza J, et al. Disposable-soma senescence mediated by
sexual selection in an ungulate. Nature 2004;432:215–218.
12. Shanley DP, Kirkwood TB. Calorie restriction and aging: A
life-history analysis. Evolution 2000;54:740–750.
13. Cichon MK, Kozlowski J. Ageing and typical survivorship
curves result from optimal resource allocation. Evol Ecol Res
14. Millar JS. Energy reserves in breeding small mammals. In:
Reproductive Energetics in Mammals, Loudon ASI, Racey
PA, eds. Oxford, Clarendon Press, pp. 231–240, 1987.
15. Heber-Katz E, et al. Spallanzani’s mouse: A model of res-
toration and regeneration. Curr Top Microbiol Immunol
16. Heber-Katz E, et al. Conjecture: Can continuous regenera-
tion lead to immortality? Studies in the MRL mouse. Re-
juvenation Res 2006;9:3–9.
17. Harman D. Aging: A theory based on free radical and ra-
diation chemistry. J Gerontol 1956;11:298–300.
18. Virtamo J, et al. Incidence of cancer and mortality following
alpha-tocopherol and beta-carotene supplementation: A
postintervention follow-up. JAMA 2003;290:476–485.
19. Skulachev, VP, Programmed death phenomena: from or-
ganelle to organism. Ann N Y Acad Sci, 2002. 959: p. 214–37.
20. Skulachev VP, Longo VD. Aging as a mitochondria-
mediated atavistic program: can aging be switched off? Ann
NY Acad Sci 2005;1057:145–164.
21. Marzetti E, Leeuwenburgh C. Skeletal muscle apoptosis,
sarcopenia and frailty at old age. Exp Gerontol 2006;41:
22. Pistilli EE, Jackson JR, Alway SE. Death receptor-associated
proapoptotic signaling in aged skeletal muscle. Apoptosis
23. Su JH, et al. Immunohistochemical evidence for apoptosis in
Alzheimer’s disease. Neuroreport 1994;5:2529–2533.
24. Vina J, et al. Mitochondrial oxidant signalling in Alzheimer’s
disease. J Alzheimers Dis 2007;11:175–181.
25. Mochizuki H, et al. Histochemical detection of apoptosis in
Parkinson’s disease. J Neurol Sci 1996;137:120–123.
26. Lev N, Melamed E, Offen D. Apoptosis and Parkinson’s
disease. Prog Neuropsychopharmacol Biol Psychiatry 2003;
27. Linnane AW, et al. Human aging and global function of
coenzyme Q10. Ann NY Acad Sci 2002;959:396–411; dis-
cussion 463–465.
28. Tatone C, et al. Age-dependent changes in the expression of
superoxide dismutases and catalase are associated with ul-
trastructural modifications in human granulosa cells. Mol
Hum Reprod 2006;12:655–660.
29. Hanson RW, Hakimi P. Born to run; the story of the PEPCK-
Cmus mouse. Biochimie 2008;90:838–842.
30. Van Remmen H, et al. Life-long reduction in MnSOD ac-
tivity results in increased DNA damage and higher inci-
dence of cancer but does not accelerate aging. Physiol
Genomics 2003;16:29–37.
31. Van Raamsdonk JM, Hekimi S. Deletion of the mitochon-
drial superoxide dismutase sod-2 extends lifespan in Cae-
norhabditis elegans. PLoS Genet 2009;5:e1000361.
32. Johnson TE, Tedesco PM, Lithgow GJ. Comparing mutants,
selective breeding, and transgenics in the dissection of ag-
ing processes of Caenorhabditis elegans. Genetica 1993;91:
33. Liu X, et al. Evolutionary conservation of the clk-1-
dependent mechanism of longevity: Loss of mclk1 increases
cellular fitness and lifespan in mice. Genes Dev 2005;19:
34. Lapointe J, Hekimi S. Early mitochondrial dysfunction
in long-lived Mclk1þ=mice. J Biol Chem 2008;283:26217–
35. Ayyadevara S, et al. Remarkable longevity and stress re-
sistance of nematode PI3K-null mutants. Aging Cell 2008;7:
36. Andziak B, O’Connor TP, Buffenstein R. Antioxidants do not
explain the disparate longevity between mice and the lon-
gest-living rodent, the naked mole-rat. Mech Ageing Dev
37. Andziak B, et al. High oxidative damage levels in the
longest-living rodent, the naked mole-rat. Aging Cell 2006;5:
38. Finch CE. Longevity, Senescence and the Genome. Uni-
versity of Chicago Press, Chicago, 1990.
39. Perez VI, et al. Is the oxidative stress theory of aging dead?
Biochim Biophys Acta 2009;1790:1005–1014.
40. Lapointe J, Hekimi S. When a theory of aging ages badly.
Cell Mol Life Sci 2009;67:1–8.
41. Mitteldorf J. Can experiments on caloric restriction be rec-
onciled with the disposable soma theory for the evolution of
senescence? Evolution Int J Org Evolution 2001;55:1902–
1905; discussion 1906.
42. Ricklefs RE, Cadena CD. Lifespan is unrelated to investment
in reproduction in populations of mammals and birds in
captivity. Ecol Lett 2007;10:867–872.
43. Le Bourg E. A mini-review of the evolutionary theo-
ries of aging. Is it the time to accept them? Dem Res 2001;4:
44. Korpelainen H. Fitness, reproduction and longevity among
European aristocratic and rural Finnish families in the 1700s
and 1800s. Proc Biol Sci 2000;267:1765–1770.
45. Grundy E, Kravdal O. Reproductive history and mortality in
late middle age among Norwegian men and women. Am J
Epidemiol 2008;167:271–279.
46. Mitteldorf J. Female Fertility and Longevity. AGE 2009; in
47. Fahy G. Precedents for the biological control of aging:
Postponement, prevention and reversal of aging processes.
In: Approaches to the Control of Aging: Building a Pathway
to Human Life Wxtension, Fahy GM, et al., eds. Springer,
New York, 2009.
48. Pletcher SD, Curtsinger JW. Mortality plateaus and the
evolution of senescence: why are old-age mortality rates so
low? Evolution 1998;52:454–464.
49. Bourke A. Kin selection and the evolution of aging. Ann Rev
Ecol Evol Syst 2007;38:103–128.
50. Mitteldorf J. Aging selected for its own sake. Evol Ecol Res,
51. Mitteldorf J. Chaotic population dynamics and the evolution
of aging: Proposing a demographic theory of senescence.
Evol Ecol Res, 2006;8:561–574.
Address correspondence to:
Josh Mitteldorf
7209 Charlton Street
Philadelphia, PA 19119
... Lithgow, 2006 Most researchers studying the evolution of aging consider aging to be non-adaptive in the sense that it appears to be a by-product or side e ect of other biological and evolutionary processes rather than an end in itself (e.g., Austad 2004;Kirkwood & Melov 2011;Cohen 2015). Increasingly, however, the ETAs have been questioned and various authors advocated aging as being evolutionarily adaptive and programmed (Libertini 1988(Libertini , 2006(Libertini , 2008Nusbaum 1996;Skulachev 1997Skulachev , 1999Skulachev , 2002Skulachev , 2011Bowles 1998Bowles , 2000Lewis 1999;Mitteldorf 2001Mitteldorf , 2004Mitteldorf , 2006Mitteldorf , 2010aMitteldorf , 2010bMitteldorf , 2014Mitteldorf , 2015Mitteldorf , 2016Mitteldorf , 2018Heininger 2002Heininger , 2012Goldsmith 2003Goldsmith , 2008Goldsmith , 2010Goldsmith , 2012Goldsmith , 2013Bredesen 2004aBredesen , 2004bTravis 2004;Longo et al. 2005;Prinzinger 2005;Mele et al. 2010;Milewski 2010;Martins 2011;Gavrilova et al. 2012;Khalyavkin 2013;Yang 2013;Mitteldorf & Martins 2014;Skulachev & Skulachev 2014;Werfel et al. 2015Werfel et al. , 2017Shilovsky et al. 2016Shilovsky et al. , 2017Shilovsky et al. , 2021Singer 2016;Lenart & Bienertová-Vašků 2017;Muller 2018;Van Raamsdonk 2018;Veenstra et al. 2018Veenstra et al. , 2020Galimov & Gems 2020Poljsak et al. 2020;Winterhalter & Simm 2022). And even staunch proponents of the ETAs (de Grey 2015; Cohen 2018) concede that there are a small number of exceptions where aging is clearly programmed. ...
... The deficits in detrusor contractility are thought to be due to inappropriate recruitment of collagen fibers, leading to increased stiffness (Cheng et al., 2018). Expulsive strength is persevered with aging, alluding to control-not tissue integrity-as the likely culprit of detrusor deficits (Mitteldorf, 2010;Smith et al., 2012). Both adrenergic and muscarinic responses are negatively impacted by aging, leading to decreased precision of neural control in the periphery (Lluel et al., 2000). ...
Full-text available
Bothersome urinary symptoms plague many older adults and disproportionally affect women. Underreporting of symptoms and general stigma/embarrassment associated with incontinence has negatively impacted the availability of treatments, as research cannot be championed if the severity of the problem is not apparent. Available therapeutics have limited efficacy and are often not recommended in aged patients. Lower urinary tract function has a long and rich history in animal studies; while much of the underlying anatomy has been described, including neural control mechanisms, the impact of aging has only just begun to be addressed. Recent work has provided strong evidence that neural control over micturition is significantly impacted by aging processes. This mini review discusses recent findings regarding how aging impacts the neural control mechanisms of micturition.
... The first, which is less central to biogerontology but remains conceptually useful, views aging as a kind of struggle against an increase in entropy within a system (Hayflick, 2007b;Kenyon, 2001): 'As we begin to lose the multiple localized battles against entropy we age, and when we ultimately lose the war we die' (West & Bergman, 2009, p. 206). While the links between entropy and aging are still debated (Demetrius, 2004;Hayflick, 2007b;Lenart & Bienertová-Vašků, 2016;Mitteldorf, 2010), theories of entropy provide a broad perspective from which to consider the effects of time on survival. For instance, according to the statistical interpretation of the Second Law of Thermodynamics (Pinker, 2018, p. 16), the mere passage of time increases the chances that a given challenge to a living system will result in a dysfunction or disorder simply because, statistically, there are more ways to break down than not. ...
While aging research and policy aim to promote ‘health’ at all ages, there remains no convincing explanation of what this ‘health’ is. In this paper, I investigate whether we can find, implicit within the sciences of aging, a way to know what health is and how to measure it, i.e. a theory of health. To answer this, I start from scientific descriptions of aging and its modulators and then try to develop some generalizations about ‘health’ implicit within this research. After discussing some of the core aspects of aging and the ways in which certain models describe spatial and temporal features specific to both aging and healthy phenotypes, I then extract, explicate, and evaluate one potential construct of health in these models. This suggests a theory of health based on the landscape of optimized phenotypic trajectories. I conclude by considering why it matters for more candidate theories to be proposed and evaluated by philosophers and scientists alike.
... It has been argued that the second law only relates to isolated systems and that since organisms are open systems the second law 27 does not apply (Mitteldorf 2010). This is false-the second law is universally applicable and always satisfied (Kondepudi and Prigogine 28 2014). ...
Full-text available
Scientists have been unable to reach a consensus on why organisms age and why they live as long as they do. Here, a multidisciplinary approach was taken in an attempt to understand the root causes of aging. Nonequilibrium thermodynamics may play a previously unappreciated role in determining longevity by governing the dynamics of degradation and renewal within biomolecular ensembles and dictating the inevitability of fidelity loss. The proposed model offers explanations for species longevity trends that have been previously unexplained and for aging-related observations that are considered paradoxical within current paradigms—for example, the elevated damage levels found even in youth within many long-lived species, such as the naked mole-rat. This framework questions whether declining selective pressure is the primary driver of aging, and challenges major tenets of the disposable soma theory. Unifying pertinent principles from diverse disciplines leads to a theoretical framework of biological aging with fewer anomalies, and may be useful in predicting outcomes of experimental attempts to modulate the aging phenotype.
... Aging, one of the most universal (and inevitable) biological phenomena, is branded by several common biological features (Medawar, 1952;Finch, 1998Finch, , 2009Heininger, 2012), while usually studied in selected model organisms (Guarente and Kenyon, 2000;Austad, 2009), primarily on unitary species. Also, aging is epitomized by assortment, sometimes contradicting ecological, biological and evolutionary theories (Kirkwood, 2005;Weinert and Timiras, 2003;Hughes and Reynolds, 2005;Jin, 2010;Mitteldorf, 2010) not yet gelled into a common and unified theory. Even as an established discipline, research into aging is still generating enormous amount of empirical results, lacking of well-founded mechanistic explanations. ...
Botryllus schlosseri, a colonial marine invertebrate, exhibits three generations of short-lived astogenic modules that continuously grow and die throughout the colony's entire lifespan, within week-long repeating budding cycles (blastogenesis), each consisting of four stages (A-D). At stage D, aging is followed by the complete absorption of adult modules (zooids) via a massive apoptotic process. Here we studied in Botryllus the protein mortalin (HSP70s member), a molecule largely known for its association with aging and proliferation. In-situ hybridization and qPCR assays reveal that mortalin follows the cyclic pattern of blastogenesis. Colonies at blastogenic stage D display the highest mortalin levels, and young modules exhibit elevated mortalin levels compared to old modules. Manipulations of mortalin with the specific allosteric inhibitor MKT-077 has led to a decrease in the modules' growth rate and the development of abnormal somatic/germinal morphologies (primarily in vasculature and in organs such as the endostyle, the stomach and gonads). We therefore propose that mortalin plays a significant role in the astogeny and aging of colonial modules in B. schlosseri, by direct involvement in the regulation of blastogenesis.
... In contrast, it has long been documented that several animal taxa, including cnidarians, sponges, bryozoans, urochordates and several chordates, do not fit with the general dogma of ageing but display continued growth and negligible senescence (Finch 1990(Finch , 1998(Finch , 2009). The same conclusion had been experimentally underscored, revealing that a wide range of environmental and biological stresses that could directly damage the body or increase the rate of wear and tear result in the paradoxical effect of rejuvenilisation and/or extended life span (Mitteldorf, 2010;Voskoboynik et al. 2002). ...
While multicellular organisms go through predictable ageing pathways, some defy progressive ageing by displaying continued growth and negligible senescence. These organisms share two archetypal life history traits: (1) sessile life mode and (2) colonial structures, conglomerates of repeated basic subunits, the modules (i.e. zooids, polyps, leaves). In many of these organisms, no boundaries exist between germ/somatic cell lines, and while the size and age of each individual basic module are usually constrained, the whole colony size/age may escape intrinsic restriction, revealing colonial entities with an unknown upper life span limit. Furthermore, colonial astogenic processes such as fission, fragmentation, fusion between ramets and partial mortality may dramatically alter actual sizes, blur predictions of age and also reveal the trait for negligible senes-cence with age. Model organisms, such as botryllid ascidians, are an indispensable tool in ageing research. In Botryllus schlosseri, ageing is marked by independent, sometimes contrasting types of ageing and senescence processes at the basic module (zooid) level, at the ramet level and at the genet level; they also exhibit novel rejuvenilisation processes (at the genet-ramet levels) following acute stress, where the stressed organism becomes younger, slowing down senescence. Colonial organisms may also present spatial and stochastic age-mosaic modules, postponement of senescence by a high regenerative power and replacement of basic modules that do not age according to classical criteria, indicating that ageing in modular organisms is possible but not obligatory. When senescence at the whole-genet level occurs, it may reflect a sharp contrast to senescence in unitary organisms. The offsetting of senescence at the basic module level may develop when vigorous totipotent stem cells exist, and there is no formal separation of soma from the germ line. The Botryllus system thus reveals, within the same colonial entity, constructed senescence/rejuvenilisation phenomena, such as semelparity versus iteroparity, programmed life span versus wear-and-tear senescence, weekly ageing of colonial modules versus whole-ramet-genet survivorship, rejuvenili-sation versus extrinsic ageing and the immortality of germ/somatic cell lines. Though still in its infancy, studying ageing and senescence processes in sessile marine colonial organisms may lead to a better understanding of the evolutionary routes of senescence.
... Moreover, all evolutionary theories of programmed aging posit that the evolutionary force actively limits organismal lifespan at an age unique to each species (Skulachev, 1999a(Skulachev, ,b, 2001(Skulachev, , 2002aLongo et al., 2005;Skulachev and Longo, 2005;Severin et al., 2008;Ljubuncic and Reznick, 2009;Mitteldorf, 2010Mitteldorf, , 2012Goldsmith, 2011Goldsmith, , 2012Goldsmith, , 2014Trindade et al., 2013). All these theories are based on the premise that natural selection resulted in preferential reproduction of those members of various species that have evolved certain mechanisms for limiting their lifespans in a species-specific fashion and upon reaching a species-specific age (Libertini, 1988;Skulachev, 1997Skulachev, , 1999aSkulachev, ,b, 2001Longo et al., 2005;Goldsmith, 2008Goldsmith, , 2011Goldsmith, , 2012Goldsmith, , 2014. ...
Full-text available
Exogenously added lithocholic bile acid and some other bile acids slow down yeast chronological aging by eliciting a hormetic stress response and altering mitochondrial functionality. Unlike animals, yeast cells do not synthesize bile acids. We therefore hypothesized that bile acids released into an ecosystem by animals may act as interspecies chemical signals that generate selective pressure for the evolution of longevity regulation mechanisms in yeast within this ecosystem. To empirically verify our hypothesis, in this study we carried out a 3-step process for the selection of long-lived yeast species by a long-term exposure to exogenous lithocholic bile acid. Such experimental evolution yielded 20 long-lived mutants, 3 of which were capable of sustaining their considerably prolonged chronological lifespans after numerous passages in medium without lithocholic acid. The extended longevity of each of the 3 long-lived yeast species was a dominant polygenic trait caused by mutations in more than two nuclear genes. Each of the 3 mutants displayed considerable alterations to the age-related chronology of mitochondrial respiration and showed enhanced resistance to chronic oxidative, thermal and osmotic stresses. Our findings empirically validate the hypothesis suggesting that hormetic selective forces can drive the evolution of longevity regulation mechanisms within an ecosystem.
Introduction Providing care for older adults who undergo mechanical ventilation (MV) is an essential practice for nursing students to gain more experience. This study was developed and conducted in order to describe the experiences of nursing students in caring for older adults with MV. Method A descriptive phenomenological method was employed. Eighteen fourth-year nursing students were recruited through purposive sampling. Face-to-face semistructured interviews were conducted. Data were analyzed using Giorgi's method. Findings Five themes were identified: delicate and difficult care, emotional feelings during the care, learning to assist older adults with MV, improved abilities, and learning support needs. Discussion Nursing students attempted to learn and improve their practical skills. They experienced emotional problems and needed to be supported by nursing instructors. This may be because of the complicated health concerns of older adults and the fact it was the students’ first experience with such patients. Therefore, preparedness to promote nursing students’ learning is recommended.
Aims: The prevalence of urinary dysfunction increases with age, yet therapies are often suboptimal. Incomplete understanding of the linkages between system, organ, and tissue domains across lifespan remains a knowledge gap. If tissue-level changes drive the aging bladder phenotype, parallel changes should be observed across these domains. In contrast, a lack of inter-domain correlation across age groups would support the hypothesis that urinary performance is a measure of the physiologic reserve, dependent on centrally-mediated adaptive mechanisms in the aging system. Methods: Male and female mice across four age groups underwent sequential voiding spot assays, pressure/flow cystometry, bladder strip tension studies, histology, and quantitative PCR analyses. The primary objective of this study was to test the impact of age on the cortical, autonomic, tissue functional and structural, and molecular domains, and identify inter-domain correlations among variables showing significant changes with age within these domains. Results: Behavior revealed diminished peripheral voiding and spot size in aged females. Cystometry demonstrated increased postvoid residual and loss of volume sensitivity, but the preservation of voiding contraction power, with almost half of oldest-old mice failing under cystometric stress. Strip studies revealed no significant differences in adrenergic, cholinergic, or EFS sensitivity. Histology showed increased detrusor and lamina propria thickness, without a change in collagen/muscle ratio. Adrb2 gene expression decreased with age. No consistent inter-domain correlations were found across age groups. Conclusions: Our findings are consistent with a model in which centrally-mediated adaptive failures to aging stressors are more influential over the aging bladder phenotype than local tissue changes.
Full-text available
This article describes a putative mechanism of aging based on the interaction of endogenous viral particles with the receptors of the innate immune system leading to producing pro-inflammatory cytokines. The innate immune response induces a complex of signaling pathways leading to senescence or tumorigenesis. The fate of a cell is depended on the activity of the p53 tumor-suppressive signaling pathway. Chronic inflammation is characterized by upregulation of the NF-kB signaling. The NF-kB protein stimulates the expression of matrix metalloproteinases (MMPs) leading to remodeling of extracellular matrix. The extracellular matrix alterations induce the loss of stem cell environment and their depletion. The innate immune system also mediates the PI3K-Akt-mTOR signaling pathway that inhibits autophagy and transforms energy metabolism providing cell senescence, high level of blood glucose, high lipid synthesis and mitochondrial alterations. The STAT3-HIF1 signaling pathway suppresses oxidative phosphorylation increasing ROS production and promoting the MAPK pathway leading to excessive cell proliferation. The increased ROS production causes the global DNA and histone demethylation contributing to retrotransposon reactivation whose activity leads to genome instability. However, the activity of retrotransposons may be partly explained by their role in adaptation. Among retrotransposons, endogenous retroviruses may be considered as an intrinsic stimulus for the innate immune system and are also able to avoid the adaptive immune system. Therefore, I consider endogenous retroviruses as promising targets in anti-aging therapies
Full-text available
ABSTRACT Ageing has a negative impact on individual fitness. From this, it has been inferred that ageing could not have arisen as an,adaptation. Two alternative hypotheses,were proposed,more,than 40years ago: (1) that ageing ,has been ,selected as a ,side-effect of fertility maximization (‘antagonistic pleiotropy’) and (2) that ageing is a manifestation,of mutational load (‘mutation accumulation’). There was good,theoretical support for these hypotheses,at the time. But in the intervening years, a body of experimental data has accumulated that is surprisingly distant from theoretical expectations. Indeed, some results may be interpreted as a direct refutation of each of the two theories. The evidence reviewed here is adduced in support of an adaptive theory, in which ageing has been selected for its own,sake. This possibility has been dismissed historically because it requires strong group selection. In a companion paper, I intend to address this objection and describe a computational,model,in which,ageing is affirmatively selected,for its contribution,to demographic,homeostasis. Keywords: ageing, group selection, hormesis, senescence.
Full-text available
One of the arguments against aging being programmed is the assumption that variation in the timing of aging-related outcomes is much higher compared to variation in timing of the events programmed by ontogenesis. The main objective of this study was to test the validity of this argument. To this aim, we compared absolute variability (standard deviation) and relative variability (coefficient of variation) for parameters that are known to be determined by the developmental program (age at sexual maturity) with variability of characteristics related to aging (ages at menopause and death). We used information on the ages at sexual maturation (menarche) and menopause from the nationally representative survey of the adult population of the United States (MIDUS) as well as published data for 14 countries. We found that coefficients of variation are in the range of 8-13% for age at menarche, 7-11% for age at menopause, and 16-21% for age at death. Thus, the relative variability for the age at death is only twice higher than for the age at menarche, while the relative variability for the age at menopause is almost the same as for the age at menarche.
Ageing is a general feature of higher organisms. Evolutionary theories of ageing rest on a gradual decline of fitness sensitivity to changes in survival and fecundity with age, so traits expressed late in life are less favoured by natural selection than those expressed early in life. From the life-history perspective, ageing may result from a scheme of optimal resource allocation in which investment in repair is lower than that required for removing all experienced damage. Here, we report the results of a dynamic programming model based on the disposable soma theory of ageing, which optimizes resource allocation to growth, reproduction and repair. The optimal allocation strategy responds to externally imposed mortality, and repair intensity Varies with age, being highest early in life, diminishing later and stopping completely well before the end of the maximum expected life. Because the level of repair varies, the rate of ageing is highest under high extrinsic mortality and lowest under low mortality. The allocation strategy shapes the survivorship curve and maximum lifespan. The model results provide an explanation of the variety of survivorship curves and maximum lifespans observed in nature. The results are discussed alongside empirical data from studies using mainly comparative approaches.
RECENTLY, in vitro studies conducted in our laboratory and others have suggested that apoptosis may have a role in the neuronal cell death associated with Alzheimer's disease (AD). To evaluate this hypothesis, the hippocampi and entorhinal cortices of AD, aged control, and surgical biopsy tissue were examined using the ApopTag system for the detection of DNA fragmentation and DNA stains to reveal nuclear morphology. Numerous neuronal nuclei displaying distinct morphological characteristics of apoptosis were present within tangle-bearing neurons as well as non-tangle-bearing neurons in AD brain, whereas few or no such nuclei were detected in control brain. Our in vivo results support the hypothesis that apoptosis may be one mechanism leading neuronal cell death in AD.
Researchers are increasingly recognizing that social effects influence the evolution of aging. Kin selection theory provides a framework for analyzing such effects because an individual's longevity and mortality schedule may alter its inclusive fitness via effects on the fitness of relatives. Kin-selected effects on aging have been demonstrated both by models of intergenerational transfers of investment by caregivers and by spatially explicit population models with limited dispersal. They also underlie coevolution between the degree and form of sociality and patterns of aging. In this review I critically examine and synthesize theory and data concerning these processes. I propose a classification, stemming from kin selection theory, of social effects on aging and describe a hypothesis for kin-selected conflict over parental time of death in systems with resource inheritance. I conclude that systematically applying kin selection theory to the analysis of the evolution of aging adds considerably to ...
Oscillatory and longitudinal time patterns play a major role in human physiology. In chronic hemodialysis patients, abnormalities in both time patterns have been observed, while time patterns can also influence the response of patients to the treatment. Abnormal oscillatory patterns have been observed for ultradian rhythms (cycle time <20 h), such as an impaired heart rate variability and circadian rhythms, as reflected by reduced day-night blood pressure differences. Conversely, the circadian rhythm of body temperature may influence the hemodynamic tolerance to the dialysis treatment. With regard to infradian (cycle time >28 h) rhythms, large seasonal differences in mortality, but also in blood pressure and interdialytic weight gain, have been observed in dialysis patients. The most important longitudinal pattern is the general reduction of life span in dialysis patients. One explanation of this phenomenon relates to the concept of accelerated aging in dialysis patients, for which there are various supportive arguments. From a phenomenological point of view, this concept translates into the high prevalence of frailty, even in young dialysis patients. A multidimensional approach appears necessary to adequately address this problem. In this review, the relevance of disturbed time patterns in dialysis patients is discussed. The changes may reflect an impairment or reduction in homeostatic/homeodynamic control in dialysis patients and also may have important prognostic and therapeutic implications.
Age-specific mortality rates level off far below 100% at advanced ages in experimental populations of Drosophila melanogaster and other organisms. This observation is inconsistent with the equilibrium predictions of both the antagonistic pleiotropy and mutation accumulation models of senescence, which, under a wide variety of assumptions, predict a "wall" of mortality rates near 100% at postreproductive ages. Previous models of age-specific mortality patterns are discussed in light of recent demographic data concerning late-age mortality deceleration and age-specific properties of new mutations. The most recent theory (Mueller and Rose 1996) argues that existing evolutionary models can easily and robustly explain the demographic data. Here we discuss the sensitivity of that analysis to different types of mutational effects, and demonstrate that its conclusion is very sensitive to assumptions about mutations. A legitimate resolution of evolutionary theory and demographic data will require experimental observations on the age-specificity of mutational effects for new mutations and the degree to which mortality rates in adjacent ages are constrained to be similar (positive pleiotropy), as well as consideration of redundancy and heterogeneity models from demographic theory.
The evolutionary theory of ageing explains why ageing occurs, giving valuable insight into the mechanisms underlying the complex cellular and molecular changes that contribute to senescence. Such understanding also helps to clarify how the genome shapes the ageing process, thereby aiding the study of the genetic factors that influence longevity and age-associated diseases.