BIOLOGICAL

BASIS OF AGING

FARHAD ZARGARI, MD, PHD

BIOLOGICAL BASIS OF AGEING

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.

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.

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).

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.

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).

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.

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.

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.

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.

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.

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.

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.

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.

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.

9-ACCUMULATIVE-WASTE THEORY

The biological theory of ageing that points to a buildup

of cells of waste products that presumably interferes with

metabolism.

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.

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).

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.

12-CROSS-LINKAGE THEORY

The idea that ageing results from accumulation of cross-

linked compounds that interfere with normal cell

function.

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).

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.

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.

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.

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.

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

with age (compensation law of mortality), and mortality

convergence is observed due to the exhaustion of initial

NONE OF THESE THEORIES TOTALLY ACCEPTED

SCIENTISTS HYPOTHESIZE IT MIGHT BE COMBINATION OF SEVERAL OR ALL