Clinical Trials Longevity & Mitochondrial

GDF15

also known as: Growth differentiation factor 15, MIC-1, NAG-1, PLAB, PTGFB

⚠ Not a peptide — a 12 kDa TGF-β superfamily protein. Rises with age and with mitochondrial stress; a potent anorexic/cachexia signal via its brainstem GFRAL/RET receptor. Active clinical development in two directions: agonism for obesity (NGM120, LY3463251) and antagonism for cachexia (ponsegromab, Pfizer Phase 3 PROACC-1 in cancer cachexia).

A 112-amino-acid mature protein (~12.5 kDa) in the TGF-β superfamily, secreted in response to cellular and mitochondrial stress. Uniquely among TGF-β family members, GDF15 signals through a non-canonical receptor — GDNF family receptor α-like (GFRAL) — expressed selectively in the area postrema and nucleus tractus solitarius of the hindbrain, which explains its striking and selective anorexic effects. Rises with aging and correlates with all-cause mortality; elevated in heart failure, cancer cachexia, and certain mitochondrial diseases. Has emerged as a drug target in two opposite directions: GDF15 analogs (e.g., NGM120, LY3463251) as anti-obesity agents, and GDF15 antagonists (ponsegromab / PF-06946860, Pfizer) as cachexia therapies — the Phase 3 PROACC-1 trial of ponsegromab in advanced cancer cachexia was ongoing as of early 2026. Not a short peptide — included here because of its prominence in aging-biomarker and metabolic grey-market discussion.

Mechanism of action

Signals through GFRAL (GDNF family receptor α-like) and the co-receptor RET, which are uniquely expressed in hindbrain area postrema and nucleus tractus solitarius neurons. Activation of these neurons produces potent appetite suppression and aversion-like behavior; this is the mechanism by which pathologically elevated GDF15 drives cachexia in cancer and chronic disease, and the mechanism being exploited therapeutically with GDF15 analogs for obesity. The restriction of GFRAL expression to hindbrain areas that lack a blood-brain barrier (circumventricular organs) means GDF15 can signal centrally without crossing the BBB, which simplifies pharmacology. GDF15 is also induced by many cellular stressors (mitochondrial dysfunction, ER stress, oxidative stress) and is considered a canonical "mitokine."

Primary uses

Cancer cachexia research (ponsegromab Phase 3; antagonism)
Obesity research (GDF15 agonists in early clinical development)
Mitochondrial-disease biomarker
Aging and all-cause-mortality biomarker (epidemiologic research)

Typical dosing

Not applicable (native GDF15 not administered; clinical agents are engineered analogs or antibodies)

⚠ Native GDF15 is not used therapeutically. Clinical candidates (ponsegromab, NGM120, long-acting GDF15 analogs) have their own dosing regimens determined by their pharmacology. Not a grey-market compound — this entry is included for reference given GDF15's prominence in aging biomarker discussion.

Regulatory status

Native GDF15 is not approved as a medicine. Engineered GDF15-pathway modulators are in active clinical development. Pfizer's ponsegromab (PF-06946860, monoclonal antibody anti-GDF15) is in Phase 3 (PROACC-1) for cancer cachexia in non-small-cell lung, pancreatic, and colorectal cancers, following a positive Phase 2 that was published in Nature Medicine in 2024. NGM Biopharmaceuticals' NGM120 (engineered anti-GFRAL antibody blocking GDF15 signaling) is in clinical development for pancreatic-cancer cachexia. Long-acting GDF15 analogs (e.g., LY3463251 from Eli Lilly) are in earlier-stage clinical development for obesity, leveraging GDF15's profound anorexic effect at the GFRAL receptor.

References

[pubmed] Mullican SE, et al. "GFRAL is the receptor for GDF15 and the ligand promotes weight loss in mice and nonhuman primates." Nat Med, 2017;23:1150-1157 (GFRAL receptor discovery).
[pubmed] Groarke JD, et al. "Ponsegromab for the Treatment of Cancer Cachexia." N Engl J Med, 2024;391:2291-2303 (Phase 2 ponsegromab in cancer cachexia).
[review] Wang D, et al. "GDF15: emerging biology and therapeutic applications for obesity and cardiometabolic disease." Nat Rev Endocrinol, 2021;17:592-607.

Related peptides

Humanin

A mitochondrial-derived peptide with neuroprotective, metabolic, and anti-apoptotic activity — one of the first signaling peptides identified as encoded by mitochondrial DNA.

MOTS-c

A mitochondrially encoded peptide studied for its effects on metabolic homeostasis, insulin sensitivity, and exercise capacity.

SHLP2

A 26-aa mitochondrial-derived peptide, the most-studied of the SHLP1–SHLP6 family (Cohen lab, USC). Preclinical data report insulin-sensitizing, antiapoptotic, and metabolic-protective effects; lower plasma levels in humans correlate with age and with type 2 diabetes. Research-only; no human clinical trials.

Quick facts

Class

⚠ Protein, not a peptide — a ~12 kDa TGF-β superfamily stress-response cytokine with a well-characterized role as a mitochondrial-stress biomarker, an anorexic / cachexia mediator, and an emerging therapeutic target in obesity and cachexia.

Subcategory

TGF-β superfamily stress-response cytokine

Sequence

112 amino acid mature protein (TGF-β superfamily); full-length prepro-GDF15 is 308 residues

Molecular weight

12500 Da

Half-life

Endogenous GDF15 has a plasma half-life of ~3 hours; engineered long-acting analogs in clinical development have half-lives supporting weekly or longer dosing intervals. — Normal endogenous plasma levels are ~300–1200 pg/mL; levels rise several-fold in cachexia, heart failure, and severe mitochondrial disease.

Evidence level

High

Disclaimer

This entry is for educational purposes only and does not constitute medical advice. Dosing information reflects published regulatory or research data and is not a recommendation. Many compounds described here are not approved for human use in the United States. Consult a licensed medical professional before considering any peptide therapy.