Growth hormone / IGF-1 axis
Upstream growth-signaling axis; reduced activity (as in Ames dwarf mice) is one of the most robust lifespan-extending interventions known in mammals, acting upstream of PI3K/Akt/mTOR.
The 'there is food and it is safe to grow' hormone signal. A hormone signaling chain (growth hormone leads to IGF-1) that sits upstream of mTOR. Turning this axis down - as seen in naturally long-lived dwarf mice - is one of the most reliable ways scientists know to extend lifespan in mammals.
Compressed here into one node; the axis spans GH→hepatic IGF-1→IGF1R/InsR→IRS→PI3K, and dwarf-mouse longevity phenotypes sit on it.
TL;DR. Growth hormone / IGF-1 axis appears in 5 curated studies in Oliver's mTOR Atlas: 4 in animal models; 1 review. No study in people is recorded for it in the Atlas yet. It has 3 interactions in the curated pathway model.
In the pathway model
| Interaction | Mechanism | Evidence | Studies |
|---|---|---|---|
| Growth hormone / IGF-1 axis activates PI3K mechanism: signal-relay · this link in full · on the map table | IGF-1 latches onto its own receptor and switches on PI3K, which builds a signalling lipid. Growth hormone works one step further back: it does not land on this receptor itself, it makes the liver release IGF-1, which then does. Insulin takes a receptor of its own into the same arm. IGF-1 docks on the IGF-1 receptor, which recruits IRS proteins and switches on PI3K to make the lipid messenger PIP3. Growth hormone does not use this receptor: it signals through its own receptor and JAK2/STAT5b, and reaches this arm mostly by inducing hepatic IGF-1. The node is drawn as one axis because the Atlas's lifespan evidence comes from interventions that lower the whole axis at once. IGF-1 docks on the IGF-1 receptor, which recruits IRS proteins and switches on PI3K to make the lipid messenger PIP3. Growth hormone does not use this receptor: it signals through its own receptor and JAK2/STAT5b, and reaches this arm mostly by inducing hepatic IGF-1. The node is drawn as one axis because the Atlas's lifespan evidence comes from interventions that lower the whole axis at once. Holds under: Compressed on purpose: growth hormone and IGF-1 are one node here, but they are not one molecule and they do not share a receptor. GH signals GHR-JAK2-STAT5b and acts on this arm largely by inducing hepatic IGF-1; patients with a homozygous STAT5b mutation have GH insensitivity with low IGF-1 and low IGFBP-3 (Kofoed 2003, PMID 13679528, outside this corpus). The dwarf-mouse lifespan evidence on this axis lowers GH and IGF-1 together, so it does not tell the two apart. Insulin enters the same arm through its own receptor and is drawn separately (INS-PI3K). plausible in people, not shown directly · settled in the literature | M | CAN2002, ROM2001 |
| Growth hormone / IGF-1 axis inhibits Longevity mechanism: functional-consequence · this link in full · on the map table | Less growth-hormone signalling, longer life in mice. Growth hormone / IGF-1 signalling acts as a brake on lifespan: mice whose GH signalling is blocked, either lifelong or from middle age, live longer and are less frail in old age. Growth hormone / IGF-1 signalling acts as a brake on lifespan: mice whose GH signalling is blocked, either lifelong or from middle age, live longer and are less frail in old age. Holds under: Mouse only. A lifelong GH-receptor-antagonist transgenic (LIST2026; an earlier study of the same line did not detect extension) and a tamoxifen-inducible whole-body Ghr knockout started at 12 months (DUR2026). mTOR signalling was not measured in either, so the route through PI3K-Akt-mTOR is inferred, not shown here. plausible in people, not shown directly · settled in the literature | A | LIST2026, DUR2026 |
| Grb10 inhibits Growth hormone / IGF-1 axis mechanism: signal-relay · this link in full · on the map table | Grb10 dampens insulin/IGF-1 signalling – which is why blocking mTOR can paradoxically make Akt more active. Stabilised Grb10 damps insulin/IGF-1 receptor signalling. This is one of two feedback arms behind the paradox that blocking mTORC1 raises Akt activity; the other is the S6K1-IRS-1 loop. Stabilised Grb10 damps insulin/IGF-1 receptor signalling. This is one of two feedback arms behind the paradox that blocking mTORC1 raises Akt activity; the other is the S6K1-IRS-1 loop. Holds under: Two mammalian cell studies (HSU2011, YUX2011). The feedback is shown in cultured cells. Its size in living tissue and in people, and how it compares with the S6K1-IRS-1 loop, are not measured. plausible in people, not shown directly · settled in the literature | M | HSU2011, YUX2011 |
Evidence at a glance
| Evidence | What it means | Studies |
|---|---|---|
| A | Animal model | 4 |
| R | Review — secondary literature, not a new result | 1 |
No direct human evidence in the Atlas for this entity yet — everything below rests on animal or molecular work.
Studies
| Year | Evidence | Study |
|---|---|---|
| 2026 | A | Growth Hormone Receptor Antagonism Extends Lifespan LIST2026 Transgenic expression of a growth hormone receptor antagonist — the G119K mutant chemistry behind the FDA-approved drug Pegvisomant — significantly extended both median and maximal lifespan in male (p = 0.044; p = 0.0037) and female mice, with maximal lifespan extended by 186 and 265 days respectively. Two-year-old antagonist mice were less frail and had greater grip strength despite increased adiposity. This is the first demonstration that antagonising GH action (as opposed to congenital GH deficiency, as in Ames/Snell dwarfs) extends mammalian lifespan — the GH/IGF-1 axis sits upstream of PI3K-Akt-mTOR, which is why it belongs in this corpus. |
| 2026 | A | Midlife Growth Hormone Receptor Ablation Extends Healthy Lifespan and Induces Sex-Specific Hepatic Transcriptional Changes at Single-Cell Resolution DUR2026 Deleting the growth hormone receptor in mice at 12 months of age, in middle age and long after development is complete, still significantly extended lifespan in both sexes without major effects on body growth. Males showed improved insulin sensitivity and were protected against age-related decline in neuromuscular performance and bone microarchitecture despite increased adiposity. Liver snRNA-seq revealed sex-dimorphic remodelling, including a shift toward feminised gene expression in male hepatocytes consistent with loss of pulsatile GH-STAT5 signalling. Important because most GH/IGF-1 longevity models are congenital: this shows a midlife start is still sufficient, which matters for translating growth-signalling (and by extension mTOR-adjacent) interventions to adults. |
| 2026 | A | Disruption of the insulin/IGF-1 signaling pathway in Caenorhabditis elegans dramatically increases male longevity and enhances reproductive health late in life ALS2026 Ubiquitous auxin-inducible degradation of the DAF-2/IGF-1 receptor in C. elegans males increases median lifespan by more than 440% — among the largest lifespan extensions reported for a single intervention — and prolongs male reproductive function late in life. Notably, degrading DAF-2 specifically in the male germline shortened lifespan, the opposite of its effect in hermaphrodites, underlining that pro-longevity nutrient-sensing interventions can act in a sex- and tissue-dependent way. |
| 1996 | A | Dwarf mice and the ageing process BRO1996 Mice with growth hormone deficiency lived substantially longer than normal littermates - founding observation linking reduced growth-signaling to mammalian longevity. |
| 2010 | R | Extending healthy life span--from yeast to humans FON2010 Influential review proposing that dietary restriction and reduced nutrient-sensing signalling (mTOR, GH/IGF-1) may slow ageing through similar, evolutionarily conserved mechanisms. Lifespan extension is shown in yeast, invertebrates, rodents and rhesus monkeys; in humans the evidence is limited to protective biomarker changes and genetic associations. |
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