3. BIOLOGICAL BASIS OF AGEING
At present, the biological basis of ageing is not fully
understood. The rate of ageing varies substantially across
different species, and this, to a large extent, is genetically
based. In model organisms and laboratory settings,
researchers have demonstrated that selected alterations
in specific genes can extend lifespan quite substantially
in nematodes, less so in fruit flies and less again in mice.
Life span extension can occur as the result of genetic
alterations that increase DNA repair, reduce oxidative
damage or reduce cell suicide (apoptosis) due to DNA
damage.
4. 1-EVOLUTIONARY THEORIES
There are several theories on the biological basis of
ageing:
Evolutionary theories: Many have argued that life-span,
like other phenotypes, is selected.
5. 2-TELOMERE THEORY
Telomeres are repeated DNA sequences at the ends of
chromosomes. They are not replicated by DNA
polymerase, and they will shorten at each cell division
unless maintained by telomerase. Telomerase adds the
telomere onto the chromosome at each cell division.
Most mammalian somatic tissues lack telomerase, so it
has been proposed (Salk 1982; Harley et al. 1990) that
telomere shortening could be a “clock” that eventually
prohibits the cells from dividing any more. When human
fibroblasts are cultured, they can divide only a certain
number of times, and their telomeres shorten. If these
cells are made to express telomerase, they can continue
dividing (Bodnar et al. 1998; Vaziri and Benchimol 1998).
6. 2-TELOMERE THEORY
Telomeres have experimentally been shown to shorten
with each successive cell division. Shortened telomeres
activate a mechanism that prevents further cell
multiplication. This may be particularly limiting to tissues
such as bone marrow and the arterial lining where cell
division occurs repeatedly throughout life. Importantly
though, mice lacking telomerase enzyme do not show a
dramatically reduced lifespan, invalidating at least
simple versions of the telomere theory of ageing.
7. 3-REPRODUCTIVE-CELL CYCLE THEORY
In essence, this theory proposes that reproductive
hormones not only regulate reproduction and
metabolism, but also modulate the life and function of
cells, and in so doing, the life of the organism, thereby
tying reproduction, metabolism and longevity together in
an evolutionary manner that allows for the continued
survival of the species. The idea that ageing is regulated
by reproductive hormones that act in an antagonistic
pleiotropic manner via cell cycle signaling, promoting
growth and development early in life to achieve
reproduction, but later in life, in a futile attempt to
maintain reproduction, become deregulated and drive
senescence (dyosis).
8. 3-REPRODUCTIVE-CELL CYCLE THEORY
The endocrine dyscrasia that follows the loss of follicles
with menopause, and the loss of Leydig and Sertoli cells
during andropause, drive aberrant cell cycle signaling
that leads to cell death and dysfunction, tissue
dysfunction (disease) and ultimately death. Moreover,
the hormones that regulate reproduction also regulate
cellular metabolism, explaining the increases in fat
deposition during pregnancy through to the deposition
of centralized adiposity with the deregulation of the HPG
axis following menopause and during andropause
(Atwood and Bowen, 2006). This theory, which
introduced a new definition of aging, has facilitated the
conceptualization of why and how aging occurs at the
evolutionary, physiological and molecular levels.
9. 4-DNA DAMAGE THEORY OF AGEING
Known causes of cancer (radiation, chemical and viral)
account for about 30% of the total cancer burden and
for about 30% of the total DNA damage. DNA damage
causes the cells to stop dividing or induce apoptosis,
often affecting stem cell pools and hence hindering
regeneration. DNA damage is thought to be the
common pathway causing both cancer and ageing.
Viral infection would appear to be the most likely cause
of the other 70% of DNA damage especially in cells that
are not exposed to smoking and sun light. It has been
argued, too, that intrinsic causes of DNA damage are
more important drivers of ageing.
10. 5-GENE LOSS THEORY OF AGEING
It has been measured that dogs lose approximately 3.3%
of the DNA in their heart muscle annually while humans
lose approximately 0.6% of their heart muscle DNA each
year. This number is very similar to the ratio of the
maximum longevities of the two species (120 years vs. 20
years, a 6/1 ratio). The comparative percentage is also
similar between the dog and human for yearly DNA loss
in the brain and lymphocytes. As stated by lead author,
Bernard L. Strehler, "....genetic damage (particularly
gene loss) is almost certainly (or probably the) central
cause of aging.
11. 5-GENE LOSS THEORY OF AGEING
Age-dependent declines in mitochondrial function are
seen in many animals, including humans (Boffoli et al.
1994). A recent report (Michikawa et al. 1999) shows that
there are “hot spots” for age-related mutations in the
mitochondrial genome, and that mitochondria with
these mutations have a higher replication frequency
than wild-type mitochondria. Thus, the mutants are able
to outcompete the wild-type mitochondria and
eventually dominate the cell and its progeny. Moreover,
the mutations may not only allow more ROS to be made,
but may make the mitochondrial DNA more susceptible
to ROS-mediated damage.
12. 5-GENE LOSS THEORY OF AGEING
The mutation rate in mitochondria is 10–20 times faster
than the nuclear DNA mutation rate (Johnson et al.
1999). It is thought that mutations in mitochondria could
(1) lead to defects in energy production,
(2) lead to the production of ROS by faulty electron transport,
and/or
(3) induce apoptosis.
13. 6-AUTOIMMUNE THEORY
The idea that ageing results from an increase in
autoantibodies that attack the body's tissues. A number
of diseases associated with ageing, such as atrophic
gastritis and Hashimoto's thyroiditis, are probably
autoimmune in this way. While inflammation is very much
evident in old mammals, even SCID mice in SPF colonies
still experience senescence.
14. 7-MTOR THEORY
mTOR, a protein that inhibits autophagy has been linked
to ageing through the insulin signaling pathway. It has
been found, in various model species, that caloric
restriction leads to longer lifespans, an effect that is likely
mediated by the nutrient-sensing function of the mTOR
pathway. mTOR functions through nutrient and growth
cues leading scientists to believe that dietary restriction
and mTOR are related in terms of longevity. When
organisms restrict their diet, mTOR activity is reduced,
which allows an increased level of autophagy.
15. 7-MTOR THEORY
This recycles old or damaged cell parts, which increases
longevity and decreases the chances of being obese.
This is thought to prevent spikes of glucose concentration
in the blood, leading to reduced insulin signalling. This
has been linked to less mTOR activation as well.
Therefore, longevity has been connected to caloric
restriction and insulin sensitivity inhibiting mTOR, which in
turns allows autophagy to occur more frequently. It may
be that mTOR inhibition and autophagy reduce the
effects of reactive oxygen species on the body, which
damage DNA and other organic material, so longevity
would be increased.
16. 8-AGEING-CLOCK THEORY
It has been argued that ageing is programmed: that an
internal clock detects a time to end investing in the
organism, leading to death. This ageing-clock theory
suggests, as in a clock, an ageing sequence is built into
the operation of the nervous or endocrine system of the
body. In rapidly dividing cells, shortening of the telomeres
would provide such a clock. This idea is in contradiction
with the evolutionary based theory of ageing.
17. 9-ACCUMULATIVE-WASTE THEORY
The biological theory of ageing that points to a buildup
of cells of waste products that presumably interferes with
metabolism.
18. 10-WEAR-AND-TEAR THEORY
The very general idea that changes associated with
ageing are the result of chance damage that
accumulates over time. “Wear-and-tear” theories of
aging are among the oldest hypotheses proposed to
account for the general scenescent phenotype
(Weismann 1891; Szilard 1959). As one gets older, small
traumas to the body build up. Point mutations increase in
number, and the efficiencies of the enzymes encoded
by our genes decrease. For example as we age,
collagen in body ages also. Causes hypertension and
other organ malfunctions.
19. 10-WEAR-AND-TEAR THEORY
Moreover, if a mutation occurred in a part of the protein
synthetic apparatus, the cell would make a large
percentage of faulty proteins (Orgel 1963). If mutations
arose in the DNA-synthesizing enzymes, the rate of
mutations would be expected to increase markedly, and
Murray and Holliday (1981) have documented such
faulty DNA polymerases in senescent cells. Likewise, DNA
repair may be important in preventing senescence, and
species whose members' cells have more efficient DNA
repair enzymes live longer (Figure 18.36; Hart and Setlow
1974). Moreover, genetic defects in DNA repair enzymes
can produce premature aging syndromes in humans (Yu
et al. 1996; Sun et al. 1998).
20. 11-ERROR ACCUMULATION THEORY
The idea that ageing results from chance events that
escape proof reading mechanisms, which gradually
damages the genetic code.
The structure of DNA is altered as people age.
Due to alterations, DNA not read correctly.
Results in transcription and translation malfunction.
Results in aging/illness/ cancer directly, or indirectly.
21. 12-CROSS-LINKAGE THEORY
The idea that ageing results from accumulation of cross-
linked compounds that interfere with normal cell
function.
22. 13-FREE-RADICAL THEORY
This major theory sees our metabolism as the cause of our
aging. According to this theory, aging is a by-product of
normal metabolism; no mutations are required. About 2–
3% of the oxygen atoms taken up by the mitochondria
are reduced insufficiently to reactive oxygen species
(ROS). These ROS include the superoxide ion, the hydroxyl
radical, and hydrogen peroxide. ROS can oxidize and
damage cell membranes, proteins, and nucleic acids.
Evidence for this theory includes the observation that
Drosophila that overexpress enzymes that destroy ROS
(catalase, which degrades peroxide, and superoxide
dismutase) live 30–40% longer than do controls (Orr and
Sohal 1994; Parkes et al. 1998).
23. 13-FREE-RADICAL THEORY
The idea that free radicals (unstable and highly reactive
organic molecules), or more generally reactive oxygen
species or oxidative stress create damage that gives rise
to symptoms we recognize as ageing. Michael Ristow's
group has provided evidence that the effect of calorie
restriction may be due to increased formation of free
radicals within the mitochondria causing a secondary
induction of increased antioxidant defence capacity.
24. 14-MISREPAIR-ACCUMULATION THEORY
Wang et al. suggest that ageing is the result of the
accumulation of "misrepair". Important in this theory is to
distinguish among "damage" which means a newly
emerging defect BEFORE any reparation has taken
place and "misrepair" which describes the remaining
defective structure AFTER (incorrect) repair. The key
points in this theory are:
1.There is no original damage left unrepaired in a living being. If
damage was left unrepaired a life-threatening condition (such
as bleeding, infection, or organ failure) would develop.
2.Misrepair, the repair with less accuracy, does not happen
accidentally. It is a necessary measure of the reparation system
to achieve sufficiently quick reparation in situations of serious or
repeated damage, to maintain the integrity and basic function
of a structure, which is important for the survival of the living
being.
25. 14-MISREPAIR-ACCUMULATION THEORY
3.Hence the appearance of misrepair increases the chance for
the survival of individual, by which the individual can live at
least up to the reproduction age, which is critically important
for the survival of species. Therefore the misrepair mechanism
was selected by nature due to its evolutionary advantage.
4.However, since misrepair as a defective structure is invisible
for the reparation system, it accumulates with time and causes
gradually the disorganisation of a structure (tissue, cell, or
molecule); this is the actual source of ageing.
5.Ageing hence is the side-effect for survival, but important for
species survival. Thus misrepair might represent the mechanism
by which organisms are not programmed to die but to survive
(as long as possible) and ageing is just the price to be paid.
26. 15-RELIABILITY THEORY OF AGEING AND
LONGEVITY
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-ageing elements (with a constant
failure rate) will nevertheless deteriorate (fail more often)
with age, if these systems are redundant in irreplaceable
elements. Ageing, therefore, is a direct consequence of
systems redundancy. Reliability theory also predicts the
late-life mortality deceleration with subsequent levelling-
off, as well as the late-life mortality plateaus, as an
inevitable consequence of redundancy exhaustion at
extreme old ages.
27. 15-RELIABILITY THEORY OF AGEING AND
LONGEVITY
The theory explains why mortality rates increase
exponentially with age (the Gompertz law) in many
species, by taking into account the initial flaws (defects)
in newly formed systems. It also explains why organisms
"prefer" to die according to the Gompertz law, while
technical devices usually fail according to the Weibull
(power) law. Reliability theory allows to specify conditions
when organisms die according to the Weibull distribution:
organisms should be relatively free of initial flaws and
defects. The theory makes it possible to find a general
failure law applicable to all adult and extreme old ages,
where the Gompertz and the Weibull laws are just
special cases of this more general failure law. The theory
explains why relative differences in mortality rates of
compared populations (within a given species) vanish
28. NONE OF THESE THEORIES TOTALLY
ACCEPTED
SCIENTISTS HYPOTHESIZE IT MIGHT BE COMBINATION OF SEVERAL OR ALL