Intro to Aging - RS

Question 1

What is the Gompertz law of human mortality?

Answer 1

The Gompertz law states that the death rate increases exponentially with age in a protected environment where external causes of death (e.g., food shortage, infectious diseases, etc.) become negligible.

Question 2

What is the mean lifespan?

Answer 2

The age at which 50% of the members in a cohort have died

Question 3

How is aging defined?

Answer 3

An overall progessive impairment of the functions of organs and tissues which ultimately converts healthy young adults into less healthy older ones with and increasing risk of illness.

Question 4

How is aging measured?

Answer 4

No reliable biomarkers better than chronological age for individuals. Measure aging at the population level.

Question 5

What does the “programmed” theory of aging say? What do we now believe?

Answer 5

Evolution selected genes that make us age. We get old and die so our progeny will have resources (This theory is under debate now). We now believe that aging results from a decline in the force of natural selection on traits acting in late life.

Question 6

What is the mutation accumulation theory of aging?

Answer 6

predicts that because of extrinsic mortality and the rarity of aged animals in a natural population, the force of selection is too weak to oppose the accumulation of germ- line mutations with late-acting deleterious effects. There is a selection shadow.

Question 7

What is the disposal soma theory of aging?

Answer 7

Successful reproduction limits the time allocated to damage repair at the cellular level. Soma could be disposed of once reproduction had occurred. Aging is driven by reduced soma maintenance and repair, as a tradeoff of reproduction success.

Question 8

What is the antagonistic pleiotropy theory of aging?

Answer 8

antagonistic pleiotropy means that a process beneficial early in life might become detrimental later in life when the forces of evolutionary selection have ended.
For example, bone calcification is important for fitness in young but causes calcification of arteries and myocardiac infaction in old.

Question 9

Why do mice live 4 years while the naked mole rat lives 30 years?

Answer 9

Less predation leads to less selection on successful reproduction which leads ultimately to an extended lifespan.

Question 10

Why study aging?

Answer 10

Aging is the greatest single risk factor of many diseases

Question 11

What is the hypothesis associated with increasing healthspan?

Answer 11

slowing down the aging process may delay the onset of aging-related degenerative disorders. This “compression of morbidity” may ultimately improve our healthspan.

Question 12

What causes aging?

Answer 12

Progressive molecular damage.

Question 13

How could treating aging (anti-aging treatment) affect early onset degenerative disease?

Answer 13

It is hypothesized that aging and aging-related degenerative diseases (e.g., Parkinson’s disease) are mechanistically linked. Manipulation of the aging process could be potentially used for the treatment of these diseases

Question 14

What do all 300+ theories on aging have in common?

Answer 14

All the theories agree on the point that time-dependent random molecular damage drives accumulation of cellular defects and therefore aging.

Question 15

What does the Free radical (oxidative stress) theory of aging propose?

Answer 15

the progressive mitochondrial damage by free radicals during aging results in increased production of ROS, which in turn causes further mitochondrial deterioration and global cellular damage. Cells are therefore engaged in a vicious cycle for time-dependent damage accumulation and tissue degeneration.

Question 16

Is there support for the oxidative stress theory?

Answer 16

No. Accumulating evidence appears to support the idea that oxidative stress IS NOT the driving force of aging in mice. There is higher Ox stress in naked mole rat.

Question 17

What does the mitochondrial theory of aging propose?

Answer 17

The mitochondrial theory of aging predicts that dysfunctional mitochondria may contribute to aging by affecting the following cellular processes in a manner independent of ROS. (I don’t feel like listing al of the things, they are on pg. 386. This doesn’t seem to important. You know what mitochondria do.)

Question 18

What does the cell senescence/ telomere theory of aging propose?

Answer 18

Replicative cellular senescence contributes to aging. Most somatic cells do not express telomerase and thus telomeres shorten as a result of cell proliferation.

Question 19

What is a big problem with the cell senescence/ telomere theory of aging?

Answer 19

Mice have longer telomeres than humans. Telomerase-deficient mice do not age rapidly, which strongly indicates that telomere shortening cannot account for normal aging in mice.

Question 20

What does the proteostatic stress theory of aging propose?

Answer 20

In addition to genome instability, proteome instability is believed to play an equally important role in aging. Stress induced by loss of protein homeostasis (or proteostasis), known as proteostatic stress, leads to protein dysfunction, disruption of cell membranes, the formation of toxic protein aggregates, and apoptotic or non apoptotic cell death.

Question 21

What does the somatic mutation theory of aging propose?

Answer 21

It predicts that DNA damage is the primary cause of aging. This theory is supported by evidence in human and mouse that inherited deficiencies in DNA repair and genome maintenance genes often cause premature aging.

Question 22

Do dwarf mice lacking growth hormone live longer than regular mice?

Answer 22

Yes. Mice with the knock out (KO) of Growth Hormone Receptor (GHR) live longer.

Question 23

What does Reduced IGF-1/Insulin signaling do in terms of life span?

Answer 23

It extends it.

Question 24

What does the activation of FOXO transcriptional factor do for cell survival?

Answer 24

It benefits cell survival. It increases Cellular maintenance, Stress Resistance and Metabolic homeostasis

Question 25

What does reduced mTOR signaling do for cell survival?

Answer 25

It favors cell survival. Decreasing the mTOR activation decreases cells growth and increases maintenance and repair mechanisms.

Question 26

Individuals with Laron syndrome (dwarfism) have a growth hormone deficiency, do they live longer?

Answer 26

No increase in lifespan. They are Almost free of cancer, have less DNA damage in response to H2O2, lower insulin levels, higher sensitivity to insulin, free of type 2 diabetes, but obese.

Question 27

What percentage of longevity is attributed to hereditary?

Answer 27

25%

Question 28

GWAS studies have been performed to elucidate which genes could be responsible for longevity, what were they?

Answer 28

FOXO3A- metabolic regulation and stress resistance
CETP- plasma lipid transport
APOC3- component of VLDL
TOMM40- mito. protein import

Question 29

What is the current hypothesis on the GH IGF-1/Insulin axis?

Answer 29

By reducing signaling in the GH-IIS axis, the metabolism of the organism shifts from growth and food intake to cellular maintenance and repair, which reduces the accumulation of cellular damage and extends lifespan.

Question 30

What is Hutchinson Gilford Progeria Syndrome? What defect causes it?

Answer 30

A rare disease that causes accelerated aging. HGPS is caused by mutations in the LMNA gene encoding lamin A which provides structural support to the nucleus

Question 31

What are the cellular defects associated with Hutchinson Gilford Progeria Syndrome?

Answer 31

• Elevated DNA damage. • Epigenetic alterations. • Chronic p53 signaling. •Inflammation. •Metabolic alterations.
• Autophagy deregulation. • Stem cell dysfunction. • Protein dyshomeostasis

Question 32

What is the main cause of death in patients with Hutchinson Gilford Progeria Syndrome? It is also what “segmental” means in the context of “segmental progeroid syndromes”?

Answer 32

Cardiovascular failure. “Segmental” – recapitulates cardiovascular aging, but no neurodegeneration and cancer.

Question 33

What are some of the ways that lifespan has been shown to be extended?

Answer 33

Caloric/dietary restriction.
Physical exercise.
Rapamycin.

Question 34

Caloric restriction extends lifespan in rodents, what effect does it have on Insulin/IGF-1, mTOR, FOXO, and AMPK?

Answer 34

Insulin/IGF-1 - decreased
mTOR - decreased
FOXO - Increased
AMPK - Increased
This ultimately decreased translation and increases autophagy, stress response and energy homeostasis.

Question 35

Rapamycin is an immunosuppressant, what happened in terms of lifespan to mice that were given this drug?

Answer 35

It increased longevity

Question 36

Can lifespan be extended? If yes, then how?

Answer 36

Lifespan can be extended by genetic manipulations in animal models, and is associated with genetic variants in humans.

Question 37

Can aging be delayed?

Answer 37

Aging can be delayed by nutritional and pharmacological interventions in rodents, which may be exploited to increase healthspan and to treat degenerative diseases in humans.

Question 38

Is there scientific data available to support the possibilty of extraordinary lives?

Answer 38

No scientific data available to support the possibility of extraordinary longevity.