Physiology of Senescence

Question 1

What is the difference between primary and secondary aging?

Answer 1

Primary aging is related to intrinsic changes that occur with age unrelated to disease and environmental influences.

Secondary aging is related to changes caused by the interaction of primary aging with environmental influences or disease processes

Question 2

Why is aging inescapable?

Answer 2

Mutation accumulation: Any mutations that result in a post-reproductive reduction in fitness will not be removed by natural selection if they benefit youth selective fitness.

Antagonistic pleiotropy: A gene that exerts a small pre-reproductive benefit and a large post-reproductive cost will still be selected for. P53 activating mutations (Anti-tumour, decreased lifespan)

Question 3

What is antagonistic pleiotropy?

Answer 3

A gene that exerts a small pre-reproductive benefit and a large post-reproductive cost will still be selected for. P53 activating mutations (Anti-tumour, decreased lifespan)

Question 4

What are the theories for primary aging?

Answer 4

2 theories:

Programmed theories: Neuroendocrine (Biological clock and endocrine control), Immune (Immune system is pacemaker of aging), Finite cell division (cells stop dividing due to hayflick limit after a finite number of divisions)

Wear and Tear theories:
Free radicals, DNA damage, aggregation of proteins that isn’t cleared, recycling failure (old/dysfunctional proteins are not cleared)

Question 5

How does oxidative stress cause aging?

Answer 5

They cause damage to sugars (glycation), mitochondria, and DNA

Question 6

What mechanisms of aging are caused by inadequate repair?

Answer 6

DNA damage due to deficient repair mechanisms (Telomere shortening)

Protein turnover (Ubiquitin and autophagy)

Membranes (Lipid peroxidation)

Cell number homeostasis problems (Cell removal increases due to apoptosis and necrosis but division is limited by telomeres and the Hayflick limit)

Question 7

What induces senescence in cells?

Answer 7

Telomere dysfunction

Chromatin perturbation

DNA damage

Strong mitogenic signals

These factors induce senesence phenotypes such as:

Growth arrest

Functional changes

Resistance to apoptosis

Question 8

Why is cellular senescence used to understand ageing?

Answer 8

Accumulation of senescent cells predicts lifespan (across various tissues, multiple mouse strains, both ad libitum fed and caloric restriction, gammaH2AX:PCNA

Question 9

What changes in the physiology of the human body with age?

Answer 9

Brain weight

Basal metabolism

Kidney filtration rate

Maximal breathing capacity

Question 10

What happens to body composition with aging?

Answer 10

Drop in lean body mass (muscular and skeletal mass)

Drop in total body water

Increase in adipose tissue

Question 11

What happens to cells with aging?

Answer 11

Increased DNA damage and decreased DNA repair capacity

Decreased oxidative capacity

Accelerated cell senescence

Increased fibrosis, lipofuscin accumulation (oxidised protein/lipid lysosymes)

Question 12

What is sarcopaenia?

Answer 12

During the late 30s muscle mass starts to drop at a rate of 1 - 2% mass/year.

Myofiber size and number both decrease (mostly type 2 fibers)

Number of motor units also decreases with aging

Can be caused by myogenic or neurogenic mechanisms (Inactivity leads to less type 2 fiber use. MN loss leads to atrophy.

Question 13

How can sarcopaenia be prevented?

Answer 13

Strength training increases myofiber size and muscle mass

Question 14

What happens in bones with aging?

Answer 14

Bone remodelling starts to favour osteoclast activity in middle age. Resorption starts to be quicker than formation of bone leading to progressive mass loss

Menopause accelerates loss (loss of oestrogen protective effects)

Question 15

What happens to joints with aging?

Answer 15

Joint flexibility decreases

Articular cartilage thins

Less tensile stiffness

Fatigue resistance decreases

Strength decreases

Loss of elasticity, tendency towards osteoarthritis

Question 16

What happens to the central nervous systems with aging?

Answer 16

CNS atrophy (0.1% per year from 20 to 60 years of age and 0.5% after 70)

Aggregates accumulate

Decreased neurotransmission

Cell death is seen most in the cortex and hippocampus leading to bigger ventricles.

Question 17

What happens to the peripheral nervous system with aging?

Answer 17

Reduced regenerative response (decreased number of schwann cells and increased macrophage response)

Demyelination/axonal atrophy/electropphysiology –> Slowed conduction

Damped signal transduction

Decreased beta-adrenergic and muscarinic responsiveness

Decreased response to beta-blockers

Question 18

What happens to sensory functions with aging?

Answer 18

They all deteriorate. (touch, vibration, spatial distinction, proprioception, vestibular function, hearing, vision, central processing (difficulty distinguishing spoken words from background noise)

Question 19

What happens to motor function with aging?

Answer 19

Decreased reaction time including decreased simple responses and complex responses.

Slowing of central processing also due to muscle strength decrease

Question 20

What happens to cognitive functions with learning?

Answer 20

Intelligence, memory and learning decline with advancing age

Certain types of memory deteriorate not all. Other types of memory are not lost.

Question 21

What happens to cardiovascular function with aging?

Answer 21

Vascular: Decreased arterial compliance and distensibility (higher systolic BP)

Increased cardiac afterload

Decreased ejection fraction and diastolic relaxation

Decreased intrinsic and max HR

Atrioventricular conduction time increases

Blunted baroreflex leading to postural hypotension.

Question 22

What happens to pulmonary function with age?

Answer 22

Decreased respiratory muscle strength and endurance (Atrophy of type 2a myofibers)

Lung volumes drop gradually

Decreased lung elasticity (Collagen and elastin degenerate, small airways collapse, impaired ventilation increased V/Q mismatch decreased resting PaO2)

Question 23

What happens to exercise capacity with aging?

Answer 23

Max O2 uptake declines

Muscle mass decreases

CV/pulm function drop leading to the other problems.

Decreased response to physical conditioning but skeletal muscle and CV system remain responsive to exercise in centenarians.

Question 24

What happens to kidney and urinary function with age?

Answer 24

Decreased renal mass

Decreased tubular mass

Loss of bladder capacity, void rate, and there is an increase in residual volume after urination.

Changes in Na+ load

RBF and GFR both fall with age as well.

Question 25

What are the minor GIT changes with aging?

Answer 25

Loss of skeletal muscle at both ends of GIT (minor loss of function leading to things like loss of ability to chew, swallow, and void faeces)

Changes in neurosensory feedback

Atrophy of secretory systems

Drop in liver mass and hepatic blood flow (Delayed regeneration following damage, decreased clearance of certain drugs, increased serum LDLs with advanced age)

Question 26

What happens to endocrine functions with age?

Answer 26

Pancreas: Insulin resistance, decreased glucose tolerance

Hypothalamus-pituitary: Decreases hypothalamus-induced rhythm, increased ADH release in response to osmolar stimuli.

Adrenal cortex: Cortisol and aldosterone secretion well preserved

Thyroid gland: Increased incidence of abnormalities, increased PTH levels with advancing age.

In very old people there is impaired 5’/3’-deiodinase activity and drop in T3

Question 27

What induces the changes of aging?

Answer 27

Growth hormones (drop in plasma [GH] due to decrease in peak pulsatile GnRH release)

Sex hormones (drop in sex hormones)

Question 28

What happens to gonads with aging?

Answer 28

Smaller ovarian reserve so less oestrogen and progesterone production

Leydig/sertoli cell atrophy leads to reduction in testosterone

Question 29

What happens to adrenal steroids with aging?

Answer 29

Age related decline in zona reticularis cell number

Question 30

What happens during menopause?

Answer 30

1 Drop in ovarian reserve

2 Drop in oestrogen

3 Drop in negative feedback from oestrogen

4 Increase in LH/FSH

5 Follicular recruitement increases follicular atresia results in more reduction in ovarian reserve

6 No ovarian reserve leads to drop in oestrogen