Lecture 7: Aging

* Understand major theories and mechanisms proposed to explain ageing and senescence. * Explain the roles of metabolism, ROS and DNA damage in ageing. * Describe factors that can increase lifespan including dietary restriction and hormesis. * Understand how senescent cells contribute to ageing and stem-cell dysfunction. * Explain how model organisms and genetics identify longevity pathways. * Describe the role of insulin/IGF–FOXO signalling in regulating lifespan.

Why are stem cells important in the context of ageing?

Stem cells are important because tissues require continuous repair and regeneration throughout life. During ageing endogenous stem cells gradually lose effectiveness, contributing to reduced tissue maintenance and regenerative capacity.

What is senescence?

Senescence is an age-related decline in biological function that occurs in cells, tissues and organisms.

What major question regarding ageing was highlighted in the lecture?

A major question is whether ageing results from simple wear and tear or whether it is partly controlled by genetic programmes.

Give examples supporting the wear-and-tear theory of ageing.

Examples include declining muscle function in C. elegans and physical deterioration such as worn teeth in elephants.

Give examples supporting a genetic contribution to ageing.

Examples include species differences in lifespan and programmed death after reproduction in salmon.

Explain the disposable soma theory.

The disposable soma theory proposes that organisms invest enough resources into maintenance and repair to ensure successful reproduction and care of offspring, but there is reduced evolutionary pressure to maintain tissues afterwards.

Why is there little natural selection against ageing later in life according to the disposable soma theory?

Once an organism can no longer improve survival or reproductive success of its offspring, there is little evolutionary advantage in maintaining extensive repair mechanisms.

What does antagonistic pleiotropy suggest regarding ageing?

Genes that improve reproductive success early in life may be selected even if they become harmful later in life.

What major factors promoting ageing were described in the lecture?

Metabolism, reactive oxygen species and DNA damage were described as major ageing factors.

What factors were described as increasing lifespan?

Dietary restriction, environmental stresses and signals from the somatic gonad were identified as lifespan-extending factors.

Explain the rate-of-living theory.

The rate-of-living theory proposes that organisms with high metabolic rates age more rapidly and therefore have shorter lifespans.

What observations support the rate-of-living theory?

Larger animals often live longer and cold-blooded animals may live longer at lower temperatures.

What are reactive oxygen species (ROS)?

ROS are highly reactive molecules generated during metabolism that can damage proteins, DNA and cellular structures.

Why was the ROS theory described as more complex than originally expected?

Experimental manipulations of ROS have produced contradictory findings rather than consistently supporting ROS as a direct cause of ageing.

What evidence challenged the simple ROS theory?

In worms paraquat and juglone treatment increased lifespan, glucose restriction increased oxidative stress while extending lifespan and mitochondrial mutants also extended lifespan.

Why was “dose” emphasised in relation to ROS?

Low and high levels of ROS can produce different biological effects, meaning ROS effects are context dependent rather than uniformly harmful.

What is hormesis?

Hormesis describes the idea that low levels of stress activate protective mechanisms that increase resistance and potentially extend lifespan.

Why were ROS described as acting like a fire alarm?

Normal ROS levels may alert cells to stress and activate protective responses rather than simply causing damage.

Why might high antioxidant levels not always be beneficial?

Excessive antioxidant activity may suppress useful ROS signalling and prevent activation of protective mechanisms.

Describe the DNA damage theory of ageing.

The DNA damage theory proposes that DNA damage accumulates over time and contributes to functional decline and ageing.

Why did some findings challenge the simple DNA damage theory?

Mice with high mutation rates did not necessarily age faster, suggesting mutation accumulation alone may not fully explain ageing.

How might PARP contribute to ageing?

PARP responds to DNA damage but consumes NAD during repair activity, potentially leading to NAD depletion.

Why might NAD depletion contribute to ageing?

NAD is important for cellular metabolism and repair processes, so depletion may impair normal cellular function.

What happens to cells experiencing extensive DNA damage?

Cells with extensive DNA damage may become senescent cells.

How may senescent cells contribute to ageing?

Senescent cells may accumulate and disrupt tissue function, increase inflammation and interfere with stem-cell repair mechanisms.

What does SASP stand for and why is it important?

SASP stands for Senescence Associated Secretory Phenotype and refers to secretion of inflammatory molecules that may contribute to chronic inflammation.

How might senescent cells interfere with stem-cell function?

Senescent cells may occupy stem-cell niches and prevent effective tissue regeneration.

What are senolytics?

Senolytics are treatments designed to selectively remove senescent cells.

How does dietary restriction affect lifespan?

Dietary restriction increases lifespan across many model organisms and does not simply work by reducing metabolic damage.

What lifespan extension example from dietary restriction was discussed?

Rats subjected to dietary restriction in early experiments showed approximately 40% lifespan extension.

Why are model organisms useful for ageing research?

Model organisms have short lifespans, genetically similar populations and are experimentally accessible.

Why are long-lived mutants easier to identify than short-lived mutants?

Short lifespan may result from developmental defects rather than ageing itself, whereas long-lived mutants are more directly associated with mechanisms regulating lifespan.

Which pathways identified through forward genetics were discussed?

IGF signalling, TOR signalling and sirtuin pathways were highlighted.

How has IGF signalling been linked to lifespan?

Reduced IGF signalling has been associated with lifespan extension in model organisms and human longevity studies.

What role does FOXO play downstream of insulin signalling?

FOXO regulates antioxidant and metabolic genes and increases resistance to oxidative stress.

Name antioxidant genes regulated downstream of FOXO signalling.

Superoxide dismutase, metallothionine, catalase and glutathione S-transferase were highlighted.