Aging is a fascinating topic that has interested philosophers and scientists for centuries.

1. Nitin
MSc Medical Biochemistry
AIIMS Rishikesh

2. What is AGING ?
 Aging is the progressive accumulation of changes with time ,
associated with or responsible for the ever increasing
susceptibility to disease and death which accompanies
advancing age “ it is a time related deterioration process “
 These changes create a normal physiologic decline seen in
middle and late adulthood.

3.  senescence
The process by which a cell looses its ability to divide, grow, and
function.
This loss of function ultimately ends in death
A degenerative process, only
Has no positive features.

4. Gerontology :
 it concerned with the changes that occur between maturity and death along
with factors that influence these changes.
Geriatrics:
It focuses on the healthcare of the elderly people and promote health by
preventing and treating diseases and disabilities in older adults.older

5. Maximum lifespan :
 the maximum life-span is the maximum numbers of years an individual of a
given species has been known to survive.
Longevity: it is expected life-span for those persons who survived
infancy, the numbers of years you lived is longevity
organisms Maximum life-span
human 122.5 years
tortoises 150 years
Domestic dog 20 years
Mice Less than 1 year
Fruit fly 3 months

6. Total four sets of genes are well known to be involved in the aging and its
prevention
These genes help in aging and also helps in prevention of aging ( if they work
on proper bases , delayed aging )
1.) DNA repair enzymes:
a) ROS generation
b) telomerase and p53
2.) proteins of the insulin signalling pathway
3.) proteins in the mTORC1 signalling pathway (a cascade that regulates
translation)
4.) chromatin remodeling enzymes

7. DNA repair enzymes :
critically important in preventing senescence
A study says” individuals of species whose cells have more efficient DNA
repair enzymes live longer
Progerias: “premature aging syndrome”
 it is caused by mutations that
 prevent the functioning of
 DNA repair enzymes

8. It proposed to account for the human senescent phenotype:
Aging is simply the accumulative and universal deteriorative processes such
as oxidation, molecular damage , wear and tear , or accumulation of adverse
by products that happens everyday
At the molecular level , the number of point mutations increases with age ,
and the efficiency of enzymes encoded by our genes dicreases.
If mutations occur in the genes encoding transcriptional or translation
proteins , the cell may make an even greater number of faulty proteins.

9. Water is a weak nucleophile
It is ubiquitous and present in high concentration , react with susceptible
target.

10. Nucleotide bases cytosine , adenine and guanine are each susceptible to
hydrolytic attack in which amino group is replaced by a carbonyl to form
uracil, hypoxanthine and xanthine respectively

11. Reactive oxygen species (ROS) generated in our metabolism
In our body, 2-3% of oxygen atoms utilized by our mitochondria and can
reduce oxygen atom into reactive oxygen species
 superoxide ions
 hydroxyl (free) –radicals
 hydrogen peroxide
So, one of the mythical factor in order to reduce or slow down the aging is eat
less - the more you eat , the more you age.
and the more you age , the more you shorter your life-span.

12. Catalase and super dismutase – Distruct the reactive oxygen species
Scientists observed on fruit flies and Nematades, and overexpressing the
enzymes that destroy reactive oxygen species like significant longer than do
control animals.
control Test
Fruit-flies
&
nematodes
Fruit-flies
&
nematodes
Normal level
of catalase &
S.D
Overexpressed
level of
catalase & S.D
Distruction
of ROS
Distruction amount
is high , because in
this catalase and
S.D levels are
overexpressed
Fast aging
process
Slow aging
process

13. Aging is an effect of an imbalance of free-radicals and antioxidant levels.
Antioxidant : molecules that fight free-radicals in our body
Free-radicals, are compounds that can cause harm if their level becomes too
high in our body.
Antioxidants are also synthesized inside the body as [GSH,NADH,NADPH]
high ROS fast aging
low ROS slow aging
high antioxidant level slow aging
low antioxidant level fast aging

14. Ultraviolet radiation can be extremely
damaging:
Sunlight can damage nucleotide bases of DNA and RNA
 the formation of thymine dimer in DNA, cross-linkage of proteins and free-
radical generation.
Thus, prolonged exposure to intense sunlight can lead to the accumulation of
multiple DNA lesions that can over-whelm a cell’s intrinsic capacity, leading
to the development of myelomas

15. Protein glycation formation of damaging
crosslinks :When amine groups in proteins are exposed to a reducing
sugar such as glucose, they may form an adduct by a process called
Glycation.
The more food you eat, the more glycation, the more damage to your proteins,
And the more you age , the more you shorter your life-span
Progressive crosslinking of collagen
network in vascular endothelium
Progressive loss of elasticity and
Thickening of blood vessels
Promotion of plaque formation

16. Free radicals and mitochondrial theory of
Aging:
 “A free radicals is any species capable of independent existence ( hence term
free) that contains one or more unpaired electron” --- Denham Harmon
(1956)
Harmon observation – life-span was inversely proportional to the metabolic
rate, and by extrapolation, respiration.
The faster is your metabolic rate, the shorter is your life-span
Means the more you eat, the more shorten is your life-span

17. Mitochondrial genome lacks surveillance and repair mechanism that help to
maintain the integrity of nuclear DNA.
Mitochondria plays a central role in sensor – response pathways that trigger
apoptosis
Genes encoded by the genome of human mitochondria

18. Age – A programmed process
“The brighter the candle the faster it burns” – metabolic rate of living
hypothesis . Raymond pearl (1920)
The more you eat, the higher your metabolic rate,
and the faster your age.
The higher metabolic rate is proportional to the shortening of your life-span.
Duration of life-span varies inversely as the rate of energy expenditure (BMR)

19. Metabolic theory of aging:
Animals differ markedly in size, longevity, heart rate, over their lifetime each
expends a similar amount of total metabolic energy per unit
Body mass, 7×105 j/g
Over the time continued generation of energy and related consumption of
oxygen leads to accumulation of ROS- induced to proteins, lipids until a
tipping point.
Reducing a sugar intake by 1 half , it will increase your life by 100%.
Calorie-restricted diet
Fewer burning calories
Fewer production of
damaging ROS

20. This factor can stop the cell cycle & cause cellular senescence in rapidly
dividing cells
Normally, p53 instruct genes to initiate cellular apoptosis, and activate DNA
repair enzymes.
One of the chief way of activating p53 is to damage the telomers, telomers is
the protective nucleoprotein caps on the tips of the chromosomes.
When p53 is activated by damaged telomeres, DNA replication halts & if the
repair doesn’t work, apoptosis is initiated

21.  If the repair system doesn’t work then p53 do the
Apoptosis of stem cell and will reduce the numbers
of cells produced and a lack of stem cells will produce
an “AGED” phenotype.
 The relationship between shortened telomeres and stem
cell depletion has been
 Seen in degenerative disease such as muscular dystrophy

22. There is a positive correlation between telomere length and longevity in
humans
: if the telomer length is high that means aging process is slow
and shorter telomers length promotes fast aging processs
There is an enzyme telomerase that maintain the integrity of telomere
Fact:
If the telomerase enzyme works properly and it prevents shortening telomere
length it helps in slow aging

23. Recent studies of mice, caenorhabditis elegans and drosophilia suggest that
there is a conserved genetic pathway that regulates aging.
This pathway directly involves the response to insulin and insulin-like growth
factors.
There is FOXO transcription factor associated with longevity.
 C. Elegans : two conditions ,
- unfavourable condition
- favourable condition

24. Unfavourable condition: food is
sufficient
 So, when the DAF2- receptor is
inactivated it helps in slow aging
process
Dauer phase
NO DAF2 gene-
activation
Aging
suspended
Metabolically
dormant
Act like a
insulin receptor
 Favourable condition : food is available
DAF2 activated
adulthood
Aging
Kimura, K. D., Tissenbaum, H. A., Liu, Y., et al. (1997). Daf-2, an insulin receptor-like gene that regulates
longevity and diapause in Caenorhabditis elegans. Science, 277(5328), 942–
946. https://doi.org/10.1126/science.277.5328.942

25.  A possible pathway for regulating longevity. In each case, the insulin
signaling pathway inhibits the synthesis of the FOXO transcription
factor proteins that would otherwise increase cellular longevity.

26. mTOR pathway:
The insulin signaling pathway functions to lower longevity, it activates the
mTORC1.
Thus, the insulin signaling pathway depresses FOXO, and at the same time it
activates mTOR1.
insulin
Activates (inr)
Inactivates (inr)
Inhibits FOXO
(TF)
Activates
mTORC1
Activates
FOXO (TF)
Promotes fast
aging
Slow aging
process

27. mice with reduced mTORC1 levels had longer lives
If the production of mTORC1, is decreased it increases the amount of
autophagy, means the removal of damaged organelles and senescent cells.
Zidek LM, Ackermann T, Hartleben G, Eichwald S, Kortman G, Kiehntopf M, Leutz A, Sonenberg N, Wang ZQ, von
Maltzahn J, Müller C, Calkhoven CF. Deficiency in mTORC1-controlled C/EBPβ-mRNA translation improves
metabolic health in mice. EMBO Rep. 2015; 16:1022–36.
Test mice
Decreased
mTORC1 level
Longer life
Slow aging
control mice
Normal
Mtorc1 level
Fast aging

28. Chromatin modification:
Sirtuins: class of evolutionarily conserved protein deacetylases
Activation or overexpression of sirtuins provide longevity benefits in many
organisms
Sirtuins activity is linked to metabolic control, apoptosis, cell survival,
development, inflammation, and healthy aging.
Sirtuins prevent genes from being expressed at the wrong times and places ,
and they help repair chromatin breaks .
 when DNA strands break (as inevitably happens as the body ages ), sirtuin
proteins are called on to fix them and cannot attend to their usual functions.

29. Sirtuin gene repair damaged DNA
Kaeberlein M, McVey M, Guarente L. The SIR2/3/4 complex and SIR2 alone promote longevity in Saccharomyces
cerevisiae by two different mechanisms. Genes Dev. 1999; 13:2570–80. 10.1101/gad.13.19.2570
DNA
damage
Sirtuins gene
Present (+)
Slow
aging
DNA
damage
Sirtuins gene
Absent (-)
Fast
aging

30. Overview:
DNA repair enzymes - if enzymes [ ]
promotes aging[ ]
e.g- progeria ( premature aging syndrome)
ROS generation :
ROS high [ ] --- fast aging
ROS low [ ] --- slow aging
[ ]free radicals --- fast aging
[ ] free radicals --- slow aging
[ ] antioxidants --- slow aging
[ ] antioxidants --- fast aging

31. Telomerase , p53 enzyme:
maintains the integrity length of telomere
telomerase --- slow aging
telomerase --- fast aging
Insulin pathway: INR INR
inhibits FOXO FOXO (tf) activated
promote aging slow aging process

32. mTORC1 pathway :
activate INR
inhibit FOXO activate mTORC1
promotes aging
Chromatin remodeling: sirtuin gene
repair DNA
slow aging process

33.  Harper illustrated biochemistry 31 edition
 DM Vasudevan 10 edition

34. Thankyou
!!!