TGF-β Signalling

•Mechanistic— Central to fibrosis and tissue remodelling

What it is

The TGF-β superfamily includes TGF-β1/2/3, activins, BMPs, GDFs, and others. Ligands bind type-II receptors that recruit and phosphorylate type-I receptors, which phosphorylate SMAD2/3 (TGF-β arm) or SMAD1/5/8 (BMP arm). SMADs partner with SMAD4 and translocate to the nucleus to direct context-specific transcription.

Why it matters in aging

• Fibrosis: TGF-β is the driver of pathological fibrosis in liver, lung, kidney, heart, and skin — arguably the central pathway in many age-related organ failures.
• Stem-cell decline: rising systemic TGF-β with age suppresses muscle stem-cell function (heterochronic parabiosis showed reducing it restores satellite-cell activity).
• Immune tolerance: TGF-β helps maintain regulatory T-cell populations; dysregulation contributes to autoimmunity and tumour immune evasion.
• Cardiovascular: drives cardiac fibrosis after MI and in HFpEF.

Notable family members

• GDF8 (myostatin) — restrains muscle growth; therapeutic inhibition is investigated for sarcopenia.
• GDF11 — controversial parabiosis "rejuvenation" factor; initial claims of cardiac-rejuvenation activity have been disputed.
• GDF15 — stress-induced cytokine, rises with age and disease; used as a biomarker of mitochondrial dysfunction.
• Activin A — rises with age; drives muscle wasting in cancer cachexia.

Pharmacology

• Anti-TGF-β antibodies (fresolimumab) in fibrosis and oncology trials, with safety challenges.
• Pirfenidone and nintedanib — approved for idiopathic pulmonary fibrosis; multi-target with TGF-β-pathway effects.
• Bimagrumab (activin-receptor blockade) for sarcopenia — mixed trial results.

Related entries

Stem cell exhaustion, Sarcopenia, Heart failure, Chronic kidney disease.