1.05 - Cell Aging

Question 1

Define: Senescence

Answer 1

Yes. Poor tissue healing is common in diabetes mellitus. A combination of altered blood supply (↓ perfusion) and high blood glucose altering (immune) cell function.

Question 2

Define: Ageing

Answer 2

The gradual changes in the structure of any organism that occur with the passage of time, that do not result from disease or other grave accidents, and that eventually lead to the increased probability of death as the individual grows older

Question 3

What did cell culture studies highlight regarding cellular senescence?

Answer 3

That cells could only undergo a fixed number of passages –> cells could only undergo certain number of divisions –> concept of a biological clock and that this was affected by the age of the cells when the culture was commenced.
Cells did not necessarily die, but entered a vegetative state and stopped dividing.

Question 4

What are some Developmental/Genetic theories for ageing?

Answer 4

There are some accelerating ageing syndromes such as Hutchinson-Gilford Syndrome and Werner’s syndrome.
Werner’s:
- Autosomal recessive
- Adult progeria (ageing before their chronological age)
- DNA Helicase abnormality, chromosome instability and higher rates of mutation

Question 5

What is a telomere?

Answer 5

Telomeres are unique tandem repeat sequences at the end of chromosomes
TTAGGG (apparently a ‘nonsense’ code)
Up to 1000 repeats in humans

Question 6

What is Telomerase?

Answer 6

Enzyme that synthesises new telomeres at 3’ end of chromosome.
When the telomere is shortened (as in DNA replication), telomerase will add more repeats to the 3’ end
Only very small amounts of telomerase present in somatic cells which have long telomeres
Is ‘immortalised’ in germ line and tumour cells

Question 7

Describe the association between telomeres and cell division

Answer 7

Every time a cell divides, you will loose some of the telomere. Chromosome replication doesnt start right at the start of the chromosome but rather a little way inward. Therefore every replication there telomere becomes shortened.

Question 8

Describe the association between telomeres, telomerase and malignancy

Answer 8

Telomerase activity has been shown to be “immortalised” in many cancers.
Believed that the increase in telomerase activity prevents the cell entering the vegetative state by increasing telomere length so that p53 isn’t activated.
Is now a new potential therapeutic target

Question 9

What happens when the telomere becomes too short?

Answer 9

If there is no telomerase activity, the cell undergoes ~60-80 doublings before the telomere becomes too short –> then p53 etc. may be activated (cycle arrest or apoptosis)
Cell then enters vegetative state and does not replitcate

Question 10

What are some other biological mechanism implicated in ageing?

Answer 10

DNA repair problems –> random mutations accumulate –> structurally altered proteins
Protein modification –> qualitative changes in function (e.g. glycation of protein such as in diabetes)
Free radical damage/ Mitochondrial DNA –> Aerobic metabolism produces free radicals which damage various structures. Mitochondria is the site of much of this production. Mitochondria vulnerable as DNA repair not as effective as in nucleus

Question 11

What is mTOR?

Answer 11

Mechanistic target or rapamycin (mTOR) is a serene/threonine protein kinase which is a regulator of cellular growth and metabolism in response to nutrient and hormonal drives.

Question 12

What is the effect of mTOR on ageing?

Answer 12

Deletion of mTOR prolongs life (in non-mammalian species).

Has demonstrated effects on mRNA translation, autophagy, mitochondrial function, inflammation & stem cells

Question 13

What are some of the histological changes in senescence?

Answer 13

Nuclei become irregular and lobulated
Mitochondria become pleomorphic and vacuolated
Endoplasmic reticulum decreases in amount and complexity
Golgi apparatus becomes distorted
Pigment accumulation

Question 14

Describe the changes in hair with ageing

Answer 14

Hair follicle melanogenesis is tightly controlled genetically. Melanin depends upon tyrosinase activity. As hair cycles exceed n=10 (~40y), hair colour changes
Hair colour depends on the degree melanosis
Melanocytes do not migrate as readily to repopulate new hair follicles, tyrosinase activity decreases → decreased melanin production in melanocytes

Question 15

Describe Age-Related Maculopathy as it relates to ageing and senescence

Answer 15

Macular degeneration is a significant cause of blindness.
Lipofuscin deposition noted from 20 years of age and accumulates.
Appears that as load reaches a critical threshold, lipofuscin itself inhibits mitochondrial respiration whilst generating more free radicals.
Apoptosis may ensue (rods seem more vulnerable).

Question 16

Describe Fertility and Oocyte ageing

Answer 16

Female fertility decrease significantly in the late third and fourth decade
Oocytes supported in culture media show morphologic changes of apoptosis
Rate proportional to age of woman from whom collected
Changes include: shrinkage, cytoplasmic condensation, membrane blebbing, ‘apoptotic’ bodies, DNA cleavage