SN7 SHORT NOTE 5M

Describe the mechanisms of cellular ageing. Add a note on autophagy.

Pathology · 2nd Professional — Para-Clinical

Definition

Cellular ageing is the progressive accumulation of sub-lethal injury and loss of functional reserve, leading to a diminished capacity to respond to stress and eventually to cell death.

Mechanisms

Mechanism	Explanation
DNA damage	Accumulated damage from radicals and radiation with defective repair; progeria and Werner syndrome are caused by DNA repair defects
Replicative senescence	Cells can divide only a limited number of times — the hayflick limit. Each division shortens the telomeres, and when they are critically short the cell arrests. Telomerase, absent from most somatic cells, is re-expressed in cancer
Defective protein homeostasis	Reduced chaperone function and failing autophagy allow misfolded proteins to accumulate
Nutrient sensing	Calorie restriction prolongs life in many species, acting through the insulin/IGF-1 pathway and the sirtuins
Free radical damage	Cumulative oxidative damage, whose visible marker is lipofuscin

CLINICAL PEARL

Telomere shortening is a clock, and cancer stops the clock. Somatic cells lose telomere with every division and eventually arrest — a defence against unlimited proliferation. Most cancers reactivate telomerase and so escape it. Ageing and malignancy are, at this level, two sides of one mechanism.

Morphology of Ageing Cells

Irregular and abnormally lobed nuclei
Pleomorphic, vacuolated mitochondria
Reduced endoplasmic reticulum and a distorted Golgi apparatus
Accumulation of lipofuscin, the "wear and tear" pigment, giving brown atrophy of the heart and liver
Advanced glycation end products cross-link proteins such as collagen and stiffen tissue

Autophagy

The process by which a cell digests its own components within lysosomes
A survival mechanism in nutrient deprivation, recycling organelles and protein for energy
Also clears damaged organelles and misfolded protein, so its decline contributes to ageing and to neurodegeneration
Excessive autophagy can itself cause cell death, and its role in cancer is complex — restraining tumour formation but helping established tumours survive stress

Applied Aspects

Progeria (Hutchinson–Gilford) — a lamin A defect; children show the features of extreme ageing and die in adolescence of atherosclerosis
Werner syndrome — a defect of a DNA helicase, giving premature ageing from adolescence
Telomerase is a target in cancer therapy, since inhibiting it would restore the replicative limit
Advanced glycation end products are increased in diabetes and contribute to its vascular complications — effectively accelerated ageing of the vessel wall
Ageing is not itself a disease, but it reduces functional reserve in every organ, which is why an elderly patient tolerates illness, surgery and drugs so much less well

All questions in General Pathology: Cell Injury, Adaptation & Cell Death

Every Pathology chapter →