FGF21: The Fasting Hormone That Could Reshape Cellular Senescence Medicine

Fibroblast growth factor 21 (FGF21) has emerged as one of the most important hormones in metabolic and cellular senescence research. First characterised in 2000 (Nishimura et al., 2000), FGF21 is primarily produced by the liver and acts as a systemic metabolic regulator. It is activated by fasting, protein restriction, and metabolic stress, and it coordinates a whole-body response that shifts fuel utilisation from glucose to fat.

Transgenic mice that overexpress FGF21 had about 30% (males) and 40% (females) longer median survival than wild-type controls (Zhang et al., eLife, 2012). This effect on lifespan is comparable to caloric restriction, making FGF21 one of the strongest pharmacological targets for cellular senescence research.

Mechanism of Action

FGF21 signals through a receptor complex composed of FGFR1c and the co-receptor beta-klotho (Ogawa et al., 2007). This receptor system is expressed in the liver, adipose tissue, pancreas, and brain. Key downstream effects:

• Fat oxidation: In mice, PPARalpha induces FGF21 in the liver during fasting, and FGF21 in turn increases fatty acid oxidation and ketone body production (Inagaki et al., 2007; Badman et al., 2007)
• Insulin sensitisation: FGF21 enhances adiponectin secretion from adipose tissue, improving systemic insulin sensitivity in mice (Lin et al., Cell Metabolism, 2013)
• Hepatoprotection: FGF21 reduces hepatic steatosis in mice (Lin et al., 2013), making it a therapeutic target for NASH/MASH; the FGF21 analogue efruxifermin reduced liver fat in a Phase 2a trial in people with NASH (Harrison et al., 2021)
• Brown fat activation: FGF21 stimulates thermogenesis through UCP1 upregulation in brown and beige adipose tissue in mice (Fisher et al., 2012)
• Appetite modulation: In mice, FGF21 acts on the brain to reduce sugar intake via neurons in the hypothalamus (von Holstein-Rathlou et al., Cell Metabolism, 2016) and to reduce sweet and alcohol preference (Talukdar et al., 2016)

FGF21 and Cellular Senescence

Reported effects of lifelong FGF21 overexpression in mice include:

• About 30% (males) and 40% (females) longer median lifespan in FGF21-transgenic mice (Zhang et al., 2012)
• Lower circulating insulin and IGF-1, with blunted growth hormone and IGF-1 signalling in the liver, mimicking aspects of caloric restriction (Zhang et al., 2012)
• Delayed age-related shrinkage of the thymus, with more naive T cells in old mice (Youm et al., 2016)
• Trade-offs in the same long-lived mice: smaller body size, reduced bone mass and female infertility (Zhang et al., 2012)

In mice, FGF21 appears to replicate some of the metabolic effects of caloric restriction without reduced food intake, although caloric restriction itself did not raise FGF21 levels (Zhang et al., 2012). This positions it as a potential "caloric restriction mimetic" alongside compounds like rapamycin, metformin, and MOTS-c.

Pharmaceutical FGF21 Analogues

Efruxifermin is the most advanced candidate. In the Phase 2b HARMONY trial in people with MASH and moderate to severe (F2 to F3) fibrosis, 39% and 41% of patients in the two efruxifermin groups with week-24 biopsies had at least one stage of fibrosis improvement without worsening of NASH, versus 20% on placebo (Harrison et al., 2023). At 96 weeks, 49% of participants on the higher dose met this endpoint versus 19% on placebo (75% versus 24% among those with a week-96 biopsy) (Noureddin et al., Lancet, 2025). In compensated cirrhosis, the SYMMETRY trial did not show a significant reduction in fibrosis at 36 weeks, its primary endpoint (Noureddin et al., NEJM, 2025). Novo Nordisk, which completed its acquisition of Akero in December 2025 (company announcement), expects the first Phase 3 results, from the SYNCHRONY Real-World safety study, in the second half of 2026 (Novo Nordisk H1 2026 report).

ZT003 is particularly interesting because it combines GLP-1 receptor agonism with FGF21 activity, potentially addressing obesity, liver disease, and metabolic cellular senescence in a single molecule. The FDA cleared it for clinical trials in MASH in June 2025 (company announcement), and a Phase 1 study started in October 2025 (ClinicalTrials.gov NCT07184502).

Reported Interventions That Increase FGF21

While pharmaceutical FGF21 analogues are not yet available, published studies report several interventions that elevate FGF21 levels:

• Extended fasting: In humans, a 2-day fast did not change plasma FGF21, whereas 7 days of fasting raised it by about 74% (Gälman et al., Cell Metabolism, 2008). In mice, fasting induces hepatic FGF21 (Inagaki et al., 2007).
• Protein restriction: Diets low in protein increase FGF21 independently of total caloric intake: circulating FGF21 rose about 10-fold in rodents, and also increased in people after 28 days on a low-protein diet (Laeger et al., 2014). In mice, diets low in methionine also raise hepatic FGF21 (Wanders et al., 2017).
• Cold exposure: Cold activates brown adipose tissue, which released FGF21 in cold-exposed rats (Hondares et al., 2011); cold exposure also increased circulating FGF21 in humans (Lee et al., 2014).
• Acute exercise: A single bout of exercise raised serum FGF21 in mice and in healthy men running at 50% or 80% of VO2max (Kim et al., 2013).
• Ketogenic diet: In mice, a ketogenic diet raises hepatic FGF21 through PPARalpha (Badman et al., 2007), but a ketogenic diet did not change FGF21 in a human study (Gälman et al., 2008).

FGF21 in Context

FGF21 sits alongside other emerging cellular senescence targets including NAD+ restoration (NMN/NR research compounds), AMPK activation (MOTS-c), and mTOR inhibition (rapamycin). The convergence of these pathways suggests that the next generation of cellular senescence interventions will combine multiple mechanisms rather than relying on single targets.

References

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