Growth & Aging Flashcards
Learning outcomes
Growth and Ageing
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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.
Why a Life Cycle?
The Generative Programme
- 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
Endocrinology of growth
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
Endocrinology of Growth
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)
Endocrinology of Growth
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)
Senescence in the Human Life Cycle
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
Survival and Mortality Data
Hayflick’s limit
- 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
Why Do We ‘Get Old?
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
Damage from free radicals
- 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
Telomerase
- telomeres: GGGTTA repeats
- telomerase repairs
on chromosome ends
lost telomeres - telomeres are lost during replication
- telomerase expression is very low in normal somatic cells
Genetic contributors to senescence
A human example: Werner syndrome
- WNR gene encodes helicase (unwinds DNA)
- mutation of WNR impairs DNA replication & repair
Genetic contributors to senescence
- 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
Environmental contributors to senescence
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 (?)
Environmental contributors to senescence
Endocrinology of Ageing
- 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
Characteristics of Senescence
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
- Andropause?
- decline of testosterone
in elderly men - decline not universal
< - HRT controversial
- implications for prostate cancer
Social Impact of Ageing
- 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??
