Communication in the field of biogerontology is a minefield because all of the commonly
used terms have no universally accepted definitions. In a series of five annual meetings
that I chaired recently in an attempt to define common terms, the dozen or more experts
who attended could not agree on the definition of almost all of them, including “aging.”
The committee was disbanded and the communications dilemma remains.
“Aging, Bench to Bedside,” the collection of mini reviews published as a series in
this journal, is representative of this unsolved problem. Not only does the problem
result in communication failures, it also produces erroneous interpretations of research
results; illogical allocation of research funds; and misdirected scientific, economic,
social, and political policy decisions [1–3]. There is no other field of science in
which a similarly bleak situation exists.
As a consequence of the terminology dilemma, I will define for use in this editorial
the four aspects of the finitude of life: aging, the determinants of longevity, age-associated
diseases, and death. I will not discuss the latter, although even this word defies
a universally accepted definition.
The Aging Process
Age changes can occur in only two fundamental ways: by a purposeful program driven
by genes or by random, accidental events.
It is a cornerstone of modern biology that a purposeful genetic program drives all
biological processes that occur from the beginning of life to reproductive maturation.
However, once reproductive maturation is reached, thought is divided with respect
to whether the emerging aging process is a continuation of the genetic program or
whether it is the result of the accumulation of random, irreparable losses in molecular
fidelity.
The deterministic dream of 19th century physicists was torpedoed in the 20th century
with Heisenberg's discovery of the uncertainty principle. In fact, the fundamental
laws of physics can only be expressed as probabilities. The most compelling evidence
for the belief that biological aging is also a random process is that everything in
the universe changes or ages in space-time without being driven by a purposeful program.
Although there is no direct evidence that genes drive age changes, their critical
role in longevity determination is indisputable.
There is a huge body of knowledge supporting the belief that age changes are characterized
by increasing entropy, which results in the random loss of molecular fidelity, and
accumulates to slowly overwhelm maintenance systems [1–4].
Both biological systems and inanimate objects incur change over time. Living systems,
however, are, among other properties, distinguishable from inanimate objects, because
a purposeful genetic program governs the changes that occur from their beginning until
reproductive maturation. In inanimate objects, change is not programmed. It is continuous
and never ending. Whether the changes that occur in inanimate objects are called age
changes or not occurs because of the tendency for humans to view the physical world
in anthropomorphic terms.
The common denominator that underlies all modern theories of biological aging is change
in molecular structure and, hence, function. These changes are the result of entropic
changes, which is now supported by the recent reinterpretation of the Second Law of
Thermodynamics, where the belief that it only applies to closed systems has been overturned
[5].
Entropy is the tendency for concentrated energy to disperse when unhindered regardless
of whether the system is open or closed. The hindrance of entropic change is the relative
strength of chemical bonds. The prevention of chemical bond breakage, among other
structural changes, is absolutely essential for life. Through evolution, natural selection
has favored energy states capable of maintaining fidelity in most molecules until
reproductive maturation, after which there is no species survival value for those
energy states to be maintained indefinitely.
The dispersal of energy may result in a biologically inactive or malfunctioning molecule.
Energy dispersal is never entirely eliminated but it can be circumvented for varying
time periods by repair or replacement processes. The internal presence of these repair
or replacement processes represents a major difference between living and inanimate
forms.
From the standpoint of a physicist, a lowered energy state is not necessarily disorder,
because it simply results in the identical molecule with a lowered energy state. The
fact that such a molecule might be biologically inactive may not concern the physicist,
but it definitely does concern the biologist and, especially, the biogerontologist.
The aging process occurs because the changed energy states of biomolecules renders
them inactive or malfunctioning. Identical events also occur before the aging phenotype
appears, but repair and replacement processes are capable of maintaining the balance
in favor of functioning molecules; otherwise, the species would vanish. After reproductive
maturation, this balance slowly shifts to one in which molecules that lose their biologically
active energy states are less likely to be replaced or repaired. The diminution of
repair and replacement capability is further exacerbated, because the enormously complex
biomolecules that compose the repair and replacement systems also suffer the same
fate as their substrate biomolecules.
When the escalating loss of molecular fidelity ultimately exceeds repair and turnover
capacity, vulnerability to pathology or age-associated diseases increases [1,3,6].
Immortal biological systems cannot exist, if for no other reason than molecular turnover
(or dilution) insures that the molecules present at the beginning of a biological
lineage are unlikely to be present in that lineage when it reaches Avogadro's Number
of about 6 × 1023 cells. The only biological property that is long lasting on an evolutionary
time scale is the message coded in information-containing molecules, but even that
data is subject to mutation or change [7].
Although the loss of molecular fidelity is a random process, there is, nonetheless,
a strong element of uniformity, in that errors will occur first in the same families
of the most vulnerable molecules in similar cells, organs, or objects. The components
of a system in which these molecules are a part then become the weakest link in that
system. This accounts for the similarity in the aging phenotype as it progresses within
species members.
Similar events occur in aging inanimate objects where, for example, automobiles of
a particular make, model, and year of manufacture may have a greater probability of
failure in a common weakest link, such as the electrical system. In another car of
similar manufacture but different make, year, or model, molecules in the cooling or
exhaust system will suffer age changes fastest and become the most probable system
to fail first. There is, inevitably, a weakest link with the probability of failing
first in a similar component of all complex entities. This “mean time to failure”
for a cheap car might be six or seven years, and for newborns today in developed countries
their mean time to failure is in the range of 75–85 years.
In humans in developed countries, the weakest links are the cells that compose the
vascular system and those in which cancer is most probable. The molecular instability,
or aging process, that occurs in these cells is the weakest link that increases vulnerability
to these two leading causes of death. This is why knowing how fundamental age changes
occur could lead to a better understanding of the etiology of all of the leading causes
of death.
The “hypothesis that aging is due in part to mtDNA damage and associated mutations…[because
the mitochondrion] generates most cellular ROS” [8] is an excellent example of one
of the many possible active causes of the loss of molecular fidelity that characterizes
the aging process. Both active and spontaneous entropic processes described above
must be balanced by repair and turnover to insure species survival until reproductive
success.
Recent studies done using bacteria seem to support the thesis, described above, that
“damaged proteins” are the cause of age changes. When a bacterium like Escherichia
coli divides by fission, one of the two daughter lineages is “damaged enriched” and
the other has “low damage” [9]. The former are “non-culturable or genetically dead”
while the latter are “reproductively competent.” In Caulobacter crescentus, replicative
senescence has been observed [10], a phenomenon that we first described in normal
human cells more than 45 years ago [11]. The phenomenon has also been reported to
occur in E. coli and in Saccharomyces cerevisae [12]. The occurrence of replicative
senescence in normal cells appears to be a universal biological phenomenon.
The Determinants of Longevity
The second aspect of the finitude of life is longevity determination—a process that
is completely different from aging.
Unlike aging, the genome governs the processes that determine longevity. These are
the systems that synthesize molecules and repair or replace them. When the repair
or replacement systems are unable to maintain the positive balance that existed prior
to reproductive success, a tipping point is reached where the aging phenotype slowly
becomes manifest.
Aging must occur in molecules that previously existed with no age changes. It is this
prior functional state of molecules and the subsequent efficiency of their maintenance
that governs longevity determination.
Unlike the stochastic process that characterizes aging, longevity determination is
not a random process. It is governed by the level of physiological reserve reached
at the time of reproductive maturation that, through natural selection, was achieved
to better guarantee survival to that age. The determination of longevity is incidental
to the main goal of the genome, which is to govern events until reproductive maturity
occurs. Thus, the genome only indirectly governs longevity.
The variations in excess physiological capacity, repair, and turnover account for
the differences found in longevity both within and among species. One might think
of longevity determination as the energy state of molecules before they incur age
changes, and aging as the state of molecules after energy dissipation results in an
irreparable state of functional loss. Longevity determination is a genome-driven anabolic
process that addresses the question: “Why do we live as long as we do?” Aging is a
chance-driven catabolic process that addresses the question: “Why do things finally
go wrong?”
Studies on “dietary restriction” (DR) [13–15] would be better interpreted to have
contributed to our understanding of longevity determination than to our understanding
of aging. The increase in longevity found by DR does not provide proof that it directly
affects the aging process, because longevity is commonly used as the endpoint in these
studies, and not age changes.
Increased longevity also could occur if DR eliminated or delayed the appearance of
pathology, because biomarkers for aging in most animals are either unknown or not
evaluated. Furthermore, because controls are either fed ad lib, or some arbitrary
number of calories, it would be just as logical to conclude that overfed animals have
a reduced longevity as it would to conclude that DR increases longevity. Indeed, alternating
periods of feast and famine is the usual lifestyle for most animals and this is much
more likely to mimic the effects of DR. Indeed, DR research might be telling us more
about the actual longevity of feral animals absent causes of death attributable to
predation, disease, or accidents.
The many studies on gene mutations in C. elegans, drosophila, and other invertebrates
[13–15] that have led to the view that genes are involved in aging have not demonstrated
that gene manipulation has slowed, stopped, or reversed biomarkers of aging. When
all-cause mortality is used as the end point, as is done in experiments with these
animals, it cannot be assumed that age changes are being affected. These studies are
more accurately interpreted to have an impact on our understanding of longevity determination.
Furthermore, genes that govern the aging process are unnecessary for it to occur.
Just as blueprints are vital to construct a complex machine, but contain no information
describing a system to cause its aging, the genome is necessary to govern biological
development and maintenance, but it contains no instructions to cause the animal to
age. Automobiles know how to age without requiring instructions. Both ultimately fail
because of changes in molecular fidelity driven by increasing entropy.
In unicellular organisms like yeast, aging has been defined either as the length of
time that a yeast cell can survive in a nondividing state, or by the number of daughter
cells produced by a mother cell before senescence [13]. In higher animals, chronological
time is generally recognized as a poor measure of the rate of aging because of the
enormous variations in the aging phenotype among individuals. And, the number of progeny
produced before senescence occurs has never been considered to be related to aging.
It is more likely that what is being studied are longevity determinants for reasons
already given. It has been known for more than a century that longevity determinants
in invertebrates are, unlike aging, capable of manipulation.
Age-Associated Diseases
The third aspect of the finitude of life is age-associated disease. The distinction
between the aging process and age-associated disease is not only based on the definition
of aging described above, but it is also rooted in several practical observations.
Unlike any disease, age changes:
(1) Occur in every multicellular animal that reaches a fixed size at reproductive
maturity.
(2) Cross virtually all species barriers.
(3) Occur in all members of a species only after the age of reproductive maturation.
(4) 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.
(5) Occur in virtually all animate and inanimate matter.
(6) Have the same universal molecular etiology, that is, thermodynamic instability.
Unlike aging, there is no disease or pathology that shares these six qualities.
The inexorable loss of molecular fidelity that defines aging can either lead to changes
that may be nonpathological affronts to vanity, inconveniences, or simply uncomfortable.
When the same kind of molecular mischief occurs in the cells of vital organs, leading
to an increase in vulnerability to disease or pathology, treatment is required because
life may be threatened.
The fundamental aging process is not a disease but it increases vulnerability to disease.
Because this critical distinction is generally unappreciated, there is a continuing
belief that the resolution of age-associated diseases will advance our understanding
of the fundamental aging process [16]. It will not. This is analogous to believing
that the successful resolution of childhood pathologies, such as poliomyelitis, Wilms'
tumors, and iron deficiency anemia advanced our understanding of childhood development.
It did not.
It is often observed that, “The classical evolutionary biological theory of aging
tells us that senescence occurs in age-structured populations because of the decline
in the force of natural selection with age” [17]. And, a less common belief that,
“…the force of natural selection could conceivably increase with age” [17]. These
beliefs belie the fact that the forces of natural selection are constant and that
large changes usually occur only on an evolutionary time scale. What changes with
age is an animal's ability to adapt to the constant forces of natural selection.
The failure to distinguish the fundamental biology of aging (biogerontology) from
age-associated pathology (geriatric medicine), and both from longevity determinants,
is the most serious impediment to our understanding of the aging process. This failure
is exemplified best by realizing that under the rubric “Aging Research,” misled policy
makers have appropriated most available funds to research on age-associated diseases.
Yet no advance in geriatric medicine will add to our knowledge of the fundamental
biology of aging [1–3].