Growth & Aging

Question 1

Learning outcomes

Answer 1

Growth and Ageing
*
Describe human growth across the life cycle and its variation within populations.
Describe hormonal and other mechanisms which regulate human growth.
Explain why the aging process is an inevitable part of the human life cycle.
Understand cellular mechanisms that lead to aging.

Question 2

Why a Life Cycle?

Answer 2

Question 3

The Generative Programme

Answer 3

• Genome not a description of a final product
• Defines a series of simple sequential steps (like origami)
• The resultant product depends on the environment in which it is made
• No ‘final product’ ; ageing is inevitable

Answer 4

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Answer 6

Question 7

Endocrinology of growth

Answer 7

Growth Hormone (GH)
- secreted by anterior pituitary
- serves as an anabolic hormone
(i.e. promotes protein synthesis)
- stimulates cell division (hyperplasia)
and enlargement (hypertrophy)
- key targets are muscle and bone
- most effects mediated via the insulin-like growth factors (IGFs)
- IGFs from liver act in endocrine role
- IGFs also act locally in tissue of origin

Question 8

Endocrinology of Growth

Answer 8

Fetal Growth
- GH relatively unimportant
- Insulin and the IGFs most critical
- Consequent macrosomia of unmanaged diabetes mellitus (due to excess fetal insulin secretion)
- Thyroid hormones crucial for bone and muscle growth (throughout life cycle)

Question 9

Endocrinology of Growth

Answer 9

Pubertal Growth
* increased GH secretion in response to gonadal steroids
* distinct male / female GH
secretion patterns
established

• long bone growth arrested by epiphyseal plate closure (again gonadal steroids)

Answer 10

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Question 12

Senescence in the Human Life Cycle

Answer 12

Senescence is apparent from…
Physical appearance (skin, hair, posture etc)
Physical capacity
Reproductive capacity etc…
But…when are we senescent? eg, a postmenopausal woman can run a marathon, yet an arthritic, frail old man could still father a child

Answer 12

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Question 13

Survival and Mortality Data

Answer 13

Answer 14

Question 14

Hayflick’s limit

Answer 14

• all normal cells have a finite capacity to divide
• maximum of 40 - 60 x
• # of passages depends on origin of cells
• tumour cells escape
  this limitation
• telomerase may be one of the key regulators

Question 15

Why Do We ‘Get Old?

Answer 15

Ultimate reasons:
* 2nd law thermodynamics
* Disposable soma theory

Proximate reasons:
* Hayflick’ s limit
- finite # cell divisions
* Free radical damage
- metabolic by-products
* Mutation acumulation
- lifetime of errors

Question 16

Damage from free radicals

Answer 16

• Free radicals (or oxidants) are by-products of oxidative phosphorylation…
  superoxide radical (02) hydrogen peroxide (H202)
  hydroxyl radical (OH)
• In excess, free radicals damage DNA, proteins & lipids
• Cells protected by enzymatic conversion of free radicals (eg, SOD; antioxidant enzymes) to oxygen and water
• Non-enzymatic antioxidants (eg, vitamins C & E) also protect cells by scavenging oxidants

Question 16

Telomerase

Answer 16

* telomeres: GGGTTA repeats * telomerase repairs on chromosome ends lost telomeres * telomeres are lost during replication * telomerase expression is very low in normal somatic cells

Question 17

Genetic contributors to senescence

Answer 17

A human example: Werner syndrome - WNR gene encodes helicase (unwinds DNA) - mutation of WNR impairs DNA replication & repair

Question 17

Genetic contributors to senescence

Answer 17

* several genetic loci identified in worms (C. elegans), which extend lifespan when mutated * genes encoding products linked to metabolism * clk-1 mutation causes overall developmental slowdown and associated increased longevity * first mammalian gene mutation to increase longevity reported in 1999 (p66shc gene); loss of p66shc improves response to oxidative stress and increases longevity

Question 17

Environmental contributors to senescence

Answer 17

Restriction of Caloric Intake - increased longevity in rats & mice (primates?) - all of development slowed - consistent with free radical damage hypothesis - consistent with Hayflick' s limit (?)

Question 18

Environmental contributors to senescence

Answer 18

Question 19

Endocrinology of Ageing

Answer 19

1. Menopause (average age: 51 years) * decline of gonadal oestrogen * due to loss of follicles / oocytes * Y bone density * increased body fat * decreased muscle mass * vaginal atrophy / dryness * hot flushes (USA: flashes) * HRT: combined estrogen / progesterone * side effect of HRT: can 1 risk of breast cancer

Question 19

Characteristics of Senescence

Answer 19

Cellular performance compromised... I protein synthesis capacity + immune function hormone production Y muscle mass...generalised weakness respiratory function...poor endurance L bone mineral density... prone to fracture skin function...decreased wound healing

Question 19

2. Andropause?

Answer 19

* decline of testosterone in elderly men * decline not universal < * HRT controversial * implications for prostate cancer

Question 20

Social Impact of Ageing

Answer 20

* 80% of 80 year olds are chronically ill * 45% of 85 year olds require daily attention (only 14% for 65-75 y.o.) * The burden on the health system can only go higher! * Care reversal over the life cycle??