This document discusses several theories of aging at the cellular, molecular, evolutionary, and systems levels. The main cellular theories discussed are telomere shortening and free radical damage accumulation over time. Evolutionary theories proposed include mutation accumulation, antagonistic pleiotropy, and the declining force of natural selection with age. Lifestyle and future biomedical interventions are mentioned as potential ways to promote healthy aging or extend lifespan.

1. Dr Doha Rasheedy
Assistant lecturer of geriatric medicine
Geriatrics Intensive care unit
Geriatric medicine department
Ain Shams University

2.  Aging is a process of general,
irreversible, and progressive
physical deterioration that
occurs over time.

3. Theories are classified in 4
levels:
•Evolutionary
•Molecular
•Cellular
•System

4. Cellular
 Cellular senescence-
Telomere theory
 Free radical.
 Wear-and-tear.
Molecular
 Gene regulation.
 Codon restriction.
 Error catastrophe
 Somatic mutation
 Dysdifferentiation
Evolutionary
 Mutation
accumulation.
 Disposable soma
 Antagonistic
pleiotropy
System
 Neuroendocrine
 Immunologic
 Rate-of-living

5. Evolutionary

7.  Free radicals and oxidants--called reactive
oxygen species (ROS) are highly reactive
molecules that can damage all sorts of
cellular components.
 ROS can originate from exogenous sources
such as ultraviolet (UV) and ionizing
radiations or from several intracellular
sources:
1-The major source is the mitochondrial generation
of ATP energy using oxygen.
2- The peroxisomes, organelles that degrade fatty
acids .
3-Cytochrome P450 enzymes. SOR is a by-product
of many of these detoxification reactions .
4-White blood cells (phagocytes) attack germs with
a mixture of oxidants including SOR.

8. Toxic accumulation of ROS interfere with cell
communication, disturb DNA, RNA and
protein synthesis, lower energy levels and
generally impede vital chemical processes.
Free radicals come in a hierarchy (according to
their potential for damage) with the hydroxyl-
radical and the superoxide-radical at the top of
the list.

9.  To protect against oxidation there are
many different types of antioxidants,
from vitamins C and E selenium, CoQ10
and lipoic acid to enzymes such as
superoxide dismutase (SOD), catalase,
and glutathione peroxidase. Briefly,
antioxidant enzymes are capable of
degrading ROS into inert compounds
through a series of chemical reactions.
 The pineal hormone melatonin also
plays multiple antioxidant roles

10. Cell
senescence/telomere
theory.

11.  Replicative senescence is a specific type
of cellular senescence that ultimately
results from loss of telomeres (specialized
structures composed of a repeating DNA
sequence and located at the ends of each
linear chromosome; With each cell
division, a small amount of DNA is lost at
each chromosome end, resulting in shorter
telomeres, altered telomere structure, and
eventual replicative senescence.

12.  Activation of the telomerase
enzyme will regenerate telomeres,
prevent replicative senescence, and
immortalize human primary cell
cultures

13. Evidence
 Specialized immortal cell types such as stem
cells, germ cells, and T lymphocytes express
telomerase and will either maintain telomere
length or delay telomere attrition.
 all cancer cells activate telomerase or an
alternate pathway of telomere extension to
avoid replicative senescence.

15.  For structures such as teeth, it is clear that
mechanical wear and tear can contribute to
the phenotype of ageing. However, such
effects are likely to be more closely related to
chronological time than to intrinsic biological
ageing

17.  the age-related changes of the cells ability to
transfer chemicals, heat and electrical
processes causes cell impairment.
 The ageing cell membrane becomes less lipid
(less watery and more solid). This impedes its
efficiency to conduct normal function and in
particular there is a toxic accumulation of
lipofuscin .
 The cells declining efficiency also means that
the essential and regular transfer of sodium
and potassium is impaired, thus reducing
communication. It is also believed that
electrical and heat transfer is also impaired.

18.  Substances that could aid in the removal of
lipofuscin deposits and improve cellular
lipidity and communication.
Centrophenoxine (Lucidril)
 Other substances that have shown an ability
to remove lipofuscin include DMAE
(dimethylaminoethanol) and the amino-acids
Acetyl-L-Carnitine and Carnosine.

19. The Mitochondrial Decline
Theory

21.  Mitochondria are the energy generators of the
cell. They typically produce 90% or more of
all the ATP bioenergy made in the body.
 Mitochondria have their own DNA mtDNA
has no histone protection or significant
enzymes repair systems to offer free radical
protection .
 Therefore, mtDNA is far more subject to free
radical damage than nDNA.
 As mtDNA damage accumulates over the
lifetime of an individual, ATP production ,
decreases dramatically and gradually
produces a cellular energy crisis.

22. The Neuro-
endocrine Theory

24.  Hypothalamo-pituitary-adrenal (HPA)
axis I s the master regulator, the
“pacemaker” that signals the onset and
termination of each life stage.
 One of the major functions of the HPA
axis is to master the physiological
adjustments necessary for preservation
and maintenance of the internal
“homeostasis” (steady state) despite the
continuing changes in the environment

25.  During life span, chronic exposure to
severe stress from a multitude of physical,
biological, or emotional stimuli may
exhaust or weaken the capacity to adapt
and lead to the so-called “diseases of
adaptation” and death . Aging would then
result from “a decreasing ability to survive
stress”.
 One theory for the hypothalamus loss of
regulation is that it is damaged by the
hormone cortisol. Which is considered to
be responsible for stress. It is known to be
one of the few hormones that increases
with age.

26. The Cross-Linking
Theory

28.  In this theory the binding of glucose (simple
sugars) to protein, (a process that occurs under
the presence of oxygen) non-enzymatic
glycosylation causes various problems.
 The cross-linking of proteins may be
responsible for cardiac enlargement and the
hardening of collagen and atherosclerosis.
 Cross linked proteins have also been
implicated in cataract and renal disorders.
 It is also theorized that sugars binding to
DNA may cause damage that leads to
malformed cells and thus cancer.

29. The Hayflick Limit
Theory

30.  The human cell is limited in the number of
times it can divide. Part of this theory may be
affected by cell waste accumulation (The
Membrane Theory of Aging).
 The human cells ability to divide is limited to
approximately 50-times, after which they
simply stop dividing (and hence die).
 The Hayflick Limit indicates the need to slow
down the rate of cell division if we want to
live long lives. Cell division can be slowed
down by diet and lifestyle etc.

31.  The use of ribonucleic acids (RNAs, the
building-blocks of DNA), improve cell repair
processes, enhance cellular capabilities and
increase the maximum number of cell
divisions in animals and vitro tests. Human
clinical studies with RNA supplements such
as NeyGeront ® and RN13 ® indicate that
there are a number of biological,
physiological and practical improvements for
geriatric patients.
 Carnosine is another potent Hayflick Limit
extender.

32. Evolutionary Theories of
Aging:
the mutation accumulation theory
the antagonistic pleiotropy theory

33.  Aging is an inevitable result of the declining
force of natural selection with age. For
example, a mutant gene that kills young
children will be strongly selected against
(will not be passed to the next generation)
while a lethal mutation with effects confined
to people over the age of 80 will experience no
selection because people with this mutation
will have already passed it to their offspring
by that age. Over successive generations, late-
acting deleterious mutations will accumulate,
leading to an increase in mortality rates late
in life.

34.  The theory of antagonistic pleiotropy is based
on two assumptions. First, it is assumed that a
particular gene may have an effect not on one
trait only but on several traits of an organism
(pleiotropy). The second assumption is that
these pleiotropic effects may affect individual
fitness in opposite (antagonistic) ways.
 Such genes will be maintained in the
population due to their positive effect on
reproduction at young ages despite their
negative effects at old age (their negative
effects in later life will look exactly like the
aging process)

35.  Late-acting deleterious genes may
even be favored by selection and be
actively accumulated in populations
if they have any beneficial effects
early in life

37.  Today, very little can be done!
• Healthy lifestyle
• Avoid premature aging
• Prevent diseases of aging
• Caloric restriction?

38. • Non-biological lifespan extension
• Cryonics, brain uploads.
• Biological interventions
• Replacement of depleted cell populations
• Regeneration
• Stem cell treatments
• Genetic modification
• Telomerase reactivation
• Drugs that affect the aging process