L19- Hormonal control of ageing

What is ageing and how is it influenced hormonally?

• Complex biological process

• Influenced by hormonal changes

• Endocrine system responds to environment (nutrients, temperature)

• Hormones generally decline with age

Which key hormones are involved in ageing?

• Growth hormone (GH)

• IGF-1

• Estrogen

• Testosterone

What is the Disposable Soma Theory

• Resources allocated between:

  • Reproduction

  • Maintenance/repair

• Trade-off impacts longevity

What is the effect of caloric restriction (CR)?

• Extends lifespan (Weindruch, Walford)

• Acts via hormonal pathways (GH/IGF1, TOR)

What is the role of the endocrine system in ageing?

• Maintains homeostasis

• Coordinates responses to environment

• Controls lifespan via hormonal axes

What major hormonal axes regulate ageing?

• Hypothalamus–Pituitary–Liver/Muscle

• Hypothalamus–Pituitary–Gonad

• Hypothalamus–Pituitary–Adrenal (HPA)

What is the effect of hypophysectomy?

• ↓ GH and IGF-1

• Extends lifespan in animals

What is the role of glucocorticoids in ageing?

• Combined with hypophysectomy → lifespan effects

• Chronic high levels → harmful

How do GH and IGF-1 change with age?

• Levels decline

• Affect:

  • Muscle mass

  • Metabolism

  • Healthspan

What is the somatotropic axis?

• GH → IGF-1 pathway

• Central regulator of ageing

What is the relationship between IGF-1 and longevity?

• Low IGF-1 → increased longevity (some species)

• Relationship is complex and genetic-dependent

What did Rudman et al. (1990) show about GH?

• GH supplementation:

  • ↑ muscle mass

  • ↓ fat

  • “Reversed” ageing markers (~10–20 years)

What are concerns about GH supplementation?

• Misinterpretation of benefits

• Not proven anti-ageing therapy

How does GH/IGF signaling relate to ageing?

• High levels →

  • ↑ senescence

  • ↑ cancer

• Reduced signaling → lifespan extension (animals)

What is GH resistance?

Malnutrition reduces GH receptor binding

What is the PROP-1 mutation effect?

• Seen in Ames mice

• ↓ pituitary function

• Extended lifespan

What is Laron syndrome?

• GH receptor mutation

• ↓ IGF-1

• ↓ cancer incidence

What is TXNIP?

• Downstream IGF-1 target

• Linked to:

  • Autophagy

  • Protection mechanisms

What is antagonistic pleiotropy of IGF-1?

Both high and low IGF-1 can be harmful

How do central hypothalamic signals respond to leucine deprivation to regulate energy metabolism (thermogenesis)?

• Leucine deprivation is sensed in hypothalamic neurons (ARC and VMN)

• Activates signalling pathways:

  • ↓ mTORC1 → S6K1 → MC4R (melanocortin-4 receptor)

  • Activates cAMP → PKA → CREB

  • Also involves ERK1/2 and PP1 pathways

• CREB activation drives transcription of:

  • CRH (corticotropin-releasing hormone)

  • TRH (thyrotropin-releasing hormone)

• Leads to:

  • Activation of sympathetic nervous system

  • ↑ T3 (thyroid hormone)

  • ↑ UCP1 (mitochondrial uncoupling protein 1)

• Result:

  • ↑ thermogenesis and energy expenditure

How does the GCN2 signalling pathway sense amino acid deficiency and regulate mTORC1?

• Amino acid (AA) deficiency → uncharged tRNA accumulates

• Activates GCN2 kinase (via GCN1; inhibited by IMPACT)

• GCN2 phosphorylates eIF2α → activates ATF4

• ATF4 induces:

  • SLCs (amino acid transporters)

  • FGF21 (metabolic regulator)

  • Sestrin2

• Sestrin2 activates GATOR pathway:

  • GATOR2 / GATOR1 → inhibit Rag GTPases (RagA/B, RagC/D)

• Leads to inactivation of mTORC1 at lysosome (via Ragulator, SLC38A9, v-ATPase)

• Also interacts with:

  • LRS (leucine sensing)

  • Rheb (mTOR activator)

• Outcome:

  • ↓ mTORC1 activity

  • Adaptive response to AA deprivation

  • Restoration of metabolic homeostasis

What is the IGF-1 mortality relationship?

• U-shaped curve

• Optimal range: 120–160 ng/ml

What happens to sex hormones with age?

• ↓ estrogen (menopause)

• ↓ testosterone (andropause)

Effects of sex hormone decline?

• Mood changes

• ↓ bone density

• ↑ cardiovascular risk

What is the Hypothalamus-Pituitary-Gonad axis?

• Controls reproductive hormones

• Influences ageing and health

Hormonal changes in menopause?

• ↑ FSH, LH

• ↓ estrogen, progesterone, inhibin

• No ovulation

What happens in perimenopause?

• ↑ FSH

• Irregular LH

• Short follicular phase

• ↑ twins

What happens to ovarian reserve with age?

↓ primordial follicles

How does reproductive function affect lifespan?

• Young ovary transplant → ↑ lifespan

• Improves:

  • Heart

  • Bone

  • Immune

  • Kidney

Role of estrogen in longevity?

• ↑ antioxidant capacity

• Protective effects

Effects of FSH reduction?

• ↑ bone mass

• ↓ fat

• ↑ mitochondrial biogenesis

Effects of LH reduction?

↑ cognitive performance

What is the effect of testosterone decline?

• ↓ muscle and sexual function

• Replacement improves function but ↑ cancer risk

What is the effect of gonadectomy?

Associated with longer lifespan

What pathways are involved in caloric restriction?

• GH/IGF1

• mTOR

• GCN2

What does mTORC1 do?

Senses amino acid abundance

What does GCN2 do?

Senses amino acid deficiency

What is FGF21 role?

Represses mTORC1 activation

What systems regulate amino acid sensing?

• Hypothalamus

• Peripheral organs (liver, muscle, adipose)

What is GLP-1?

• Hormone released after feeding

• Regulates glucose metabolism

Effects of GLP-1?

• ↑ insulin

• ↓ glucagon

• ↑ satiety

Where are GLP-1 receptors found?

Brain, pancreas, liver, heart, intestine

Clinical relevance of GLP-1 agonists?

• Weight loss drugs (e.g., semaglutide)

• May reverse brain ageing (mice)

What is the HPA axis?

• Hypothalamus → Pituitary → Adrenal

• Regulates stress, metabolism, immunity

Key hormones in HPA axis?

• CRH

• ACTH

• Cortisol

• DHEA

Age-related HPA changes?

• Blunted circadian rhythm

• More pronounced in women, AD

Effects of chronic stress?

• Negative health outcomes

• ↑ glucocorticoids

What is hormesis?

Mild stress → beneficial

What is DHEA?

• Steroid precursor

• High levels → ↑ survival

What is melatonin’s role?

• Regulates circadian rhythm

• ↑ lifespan but ↑ tumour risk (mice)

What is AEP (δ-secretase)?

• Cleaves APP & Tau → Alzheimer’s pathology

What are key points about HRT?

• May improve:

  • CVD

  • Dementia risk

  • Bone health

• WHI study showed risks (older women)

• Timing is critical

• Evidence is controversial