L22 - Sex differences in ageing

what is the trend in life expectancy in males and females (2021)

females exceed males in every country

what are some male dominant diseases

• hearing loss

• parkinsons

• COPD

what are some female dominant diseases

• cataracts

• alzheimer’s

• autoimmune disease

How does disease incidence differ between females and males?

• Disease onset differs by sex

• Females:

  • Earlier peak in disease incidence

  • Experience more chronic conditions earlier than males

• Males:

  • Later peak in disease incidence

How do sensory and cardiovascular conditions differ between males and females?

• Hearing loss: more common in men

• Ischaemic heart disease: ↑ incidence & death in men

• Cardiac function: decline in myocytes/systolic function greater in men

How do cancer patterns differ between males and females?

• Men:

  • ↑ lung/trachea/bronchus cancers

  • ↑ colon & rectum cancer incidence/death

  • Prostate cancer = major cause of death

How do neurological and ageing-related conditions differ by sex?

• Stroke: higher incidence & death in men (esp. mid-life)

• Cognition: men decline earlier; women worse verbal ability later

• Higher incidence in women:

  • AD & other dementias

  • Vision impairment

• Your note:

  • Women have ↑ frailty & disability across age range

How do metabolic, respiratory and organ diseases differ by sex?

• Women:

  • ↑ hypertension & heart disease incidence

  • ↑ COPD

  • ↑ lung disease

  • ↑ kidney disease (incidence + death)

  • ↓ muscle strength & physical performance

How does Alzheimer’s disease differ between men and women?

• Higher incidence & death in women

• Women show worse clinical symptoms

• More brain atrophy in AD

• May contribute to female survival benefit

How does stroke risk differ between men and women?

• Overall lower hazard of stroke in women vs men (meta-analysis)

• Similar risk in older age (70–80 yrs)

• Your note:

  • Female reproductive hormones may have protective cardiovascular effects

How do lifespan-extending interventions differ by sex?

• Effects often stronger in females

• Some interventions work better in males (e.g. acarbose, 17α-estradiol)

• Differences due to hormones + metabolism

  • Females respond better to vaccines (e.g. COVID)

What are the sex differences in effects of cancer radiotherapy?

• Females:

  • Greater long-term effects (↑ mortality, morbidity, frailty)

  • Faster ageing / damage accumulation

• Mechanism:

  • Therapy-induced senescence + bystander effects

• Females respond better to therapy but have more side effects

Do hallmarks of ageing differ between males and females?

• Yes — many hallmarks show sex differences

• Often influenced by:

  • Sex hormones

  • X-linked genetics

Give examples of sex differences in hallmarks of ageing

• Telomere attrition: faster in males

  • (oestrogen → ↑ telomerase activity)

• Metabolism:

  • Oestradiol → ↑ glucose tolerance

• Your note:

  • Sex hormones drive key differences in ageing biology

Why are sex differences important in longevity and disease?

• Need to understand cell-intrinsic + systemic (hormonal) mechanisms

• Sex affects response to interventions

• Differences seen across species

• Some differences present pre-puberty (not just hormonal)

What hormones are produced by the ovaries?

• Oestrogen

• Progesterone

• Inhibin A & B

• AMH

• Oestrogen present in both sexes (higher in females)

How are female hormones regulated across the menstrual cycle?

• Controlled by FSH & LH

• Phases:

  • Follicular → Ovulation → Luteal

• Cyclical changes in:

  • Hormones

  • Body temperature

  • Endometrium

What hormonal changes occur after menopause?

• ↑ FSH & LH

• ↓ Oestradiol (oestrogen), inhibin, progesterone

• Ovulation stops

• Your note:

  • ↓ oestrogen may ↑ cardiovascular disease risk

What are the longevity benefits of maintaining reproductive function?

• oung ovary transplantation → ↑ lifespan

• Benefits include:

  • ↑ cardioprotection

  • ↑ bone density

  • ↑ renal & immune function

• Young ovaries → higher life expectancy

How does oestrogen affect ageing and longevity?

• ↑ antioxidant capacity

• Helps reduce oxidative stress

• Associated with improved lifespan (animal models)

What is the effect of 17α-oestradiol on lifespan?

• ↑ lifespan in male mice

• Potential translational issues:

  • Feminisation effects

• (Evidence mainly from animal studies)

How are male hormones regulated?

• Controlled by hypothalamus → pituitary → testes (HPG axis)

• GnRH → FSH & LH

• LH → Leydig cells → testosterone

• FSH → Sertoli cells → spermatogenesis

• Mainly produced in testes under hypothalamic control

What are the effects of testosterone on the body?

• Anabolic effects:

  • ↑ muscle, bone, blood production

• Supports multiple organ systems

• Your notes:

  • Builds structures important for life

  • High levels can be harmful

  • May suppress immune function

What are the longevity effects of testosterone in males?

• Declines with age → ↓ function

• Replacement:

  • ↑ sexual function, muscle & bone strength

  • ↑ prostate cancer risk

What is the effect of gonadectomy/castration on lifespan?

• Associated with ↑ lifespan

• Evidence from eunuchs & animal studies

  • Castration ↑ life expectancy

How does sexual selection differ between males and females?

• Sexual selection = competition for mates

• Stronger in males

• Females = “limited sex” (reproductive constraint)

• Males → more competition

How does sexual selection influence male lifespan?

• Males take more risks → ↑ mortality

• “Live fast, die young” strategy

• High environmental mortality →

  • ↓ lifespan

  • ↑ rate of ageing

How does sexual selection lead to faster ageing in males?

• ↑ investment in growth/reproduction → ↓ somatic maintenance

• Leads to faster ageing

• Evidence:

  • High mating effort → ~35% ↓ lifespan (ants, flies)

• Key idea:

  • Trade-off: reproduction vs maintenance

How does stress response differ between males and females (working hypothesis)?

• Sex-specific stress response

• Males: competitive → prioritise reproduction

• Females: protective → prioritise survival & maintenance

• Your notes:

  • Lactation = high energy cost

  • Harsh environments → shift energy to maintenance

Are females more sensitive to stress than males?

• Yes — generally greater stress responses in females

• Seen across stressors:

  • Dietary restriction

  • Radiation

  • Infection

• Linked to survival-focused biology

How might stress responses contribute to sex differences in ageing?

• Stress → cell senescence (possibly ↑ in females)

• Senescent cells → pro-inflammatory → disease

• Hypothesis:

  • Females may accumulate senescent cells earlier/more

How do female vs male cells respond to stress in terms of senescence?

• Females show greater senescent transition after stress

• ↑ DNA damage response markers vs males

• Suggests higher sensitivity to stress-induced ageing

Do females accumulate more senescent cells in gut with age?

• Yes — greater accumulation with age in females

• ↑ Lamin B1 negative cells

• ↑ HMGB1 negative cells

• Indicates ↑ senescence vs males

Do females accumulate more senescent cells in the brain (hippocampus)?

• Yes — greater age-related accumulation in females

• Seen in hippocampal regions (CA1, DG)

• ↑ senescence markers vs males

• Supports idea:

  • Females may accumulate more senescent cells with ageing

What evidence is there for sex differences in ageing in humans?

• Human Pathome (large histology dataset)

• Shows sex-specific ageing patterns

• Based on disease pathology data

• Your notes:

  • Similar findings in humans

  • Based on catalogue of disease pathology

How do ageing patterns differ between males and females in humans?

• Females: age earlier but slower

• Males: age later but faster

• Your note:

  • Males start ageing later but decline more rapidly