Fibroblast growth factor 21 (FGF21) and Longevity

#21

Dietary protein restriction elevates FGF21 levels and energy requirements to maintain body weight in lean men

Dietary protein restriction increases energy expenditure and enhances insulin sensitivity in mice. However, the effects of a eucaloric protein-restricted diet in healthy humans remain unexplored. Here, we show in lean, healthy men that a protein-restricted diet meeting the minimum protein requirements for 5 weeks necessitates an increase in energy intake to uphold body weight, regardless of whether proteins are replaced with fats or carbohydrates. Upon reverting to the customary higher protein intake in the following 5 weeks, energy requirements return to baseline levels, thus preventing weight gain. We also show that fasting plasma FGF21 levels increase during protein restriction. Proteomic analysis of human white adipose tissue and in FGF21-knockout mice reveal alterations in key components of the electron transport chain within white adipose tissue mitochondria. Notably, in male mice, these changes appear to be dependent on FGF21. In conclusion, we demonstrate that maintaining body weight during dietary protein restriction in healthy, lean men requires a higher energy intake, partially driven by FGF21-mediated mitochondrial adaptations in adipose tissue.

Open Access Paper:

https://www.nature.com/articles/s42255-025-01236-7

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#22

FGF21 protects mice from ischemic stroke, study shows

March 12, 2025

Ischemic stroke is a fatal condition caused by an arterial embolism that blocks the blood flow through the cerebral artery, frequently being a cause of mortality and disability. Fibroblast growth factor 21 (FGF21) is likely the only member of the FGF family that may cross the blood-brain barrier. Among its functions, inflammatory regulation, energy metabolism, vascular homeostasis, oxidative stress and tissue repair can be highlighted.

Open Access Paper:

FGF21, a modulator of astrocyte reactivity, protects against ischemic brain injury through anti-inflammatory and neurotrophic pathways

Ischemic stroke is a frequent cause of mortality and disability, and astrocyte reactivity is closely associated with injury outcomes. Fibroblast growth factor 21 (FGF21), an endogenous regulator, has been shown to perform pleiotropic functions in central nervous system (CNS) disorders. However, studies on neurological diseases have paid little attention to the effects and detailed mechanisms of FGF21 in astrocytes. Here, we found elevated serum levels of FGF21 in stroke patients and transient middle cerebral artery occlusion (tMCAO) mice. In the peri-infarct cortex, microglia and astrocytes serve as sources of FGF21 in addition to neurons. MRI and neurobehavioral assessments of wild-type (WT) and FGF21−/− tMCAO model mice revealed a deteriorated consequence of the loss of FGF21, with exacerbated brain infarction and neurological deficits. Additionally, combined with the pharmacological treatment of WT mice with recombinant human FGF21 (rhFGF21) after tMCAO, FGF21 was identified to suppress astrocytic activation and astrocyte-mediated inflammatory responses after brain ischemia and participated in controlling the infiltration of peripheral inflammatory cells (including macrophages, neutrophils, monocytes, and T cells) by modulating chemokines expression (such as Ccl3, Cxcl1, and Cxcl2) in astrocytes. Furthermore, rhFGF21 was shown to boost the production of neurotrophic factors (BDNF and NGF) in astrocytes, and by which rescued neuronal survival and promoted synaptic protein expression (postsynaptic density protein-95 (PSD-95), synaptotagmin 1 (SYT1), and synaptophysin) in neurons after ischemic injury. Overall, our findings implicate that FGF21 acts as a suppressor of astrocyte activation, and exerts anti-inflammatory and neurotrophic effects after ischemic brain injury through its action on astrocytes, offering an alternative therapeutic target.

https://www.nature.com/articles/s41401-024-01462-x

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#23

Research progress and strategy of FGF21 for skin wound healing

Fibroblast Growth Factor 21 (FGF21), a pivotal member of the fibroblast growth factor family, exhibits multifaceted biological functions, including the modulation of pro-inflammatory cytokines and metabolic regulation. Recent research has revealed that in impaired skin tissues, FGF21 and its receptors are upregulated and play a significant role in accelerating the wound healing process. However, the clinical application of FGF21 is severely limited by its short in vivo half-life: this factor is often degraded by enzymes before it can exert its therapeutic effects. To address this limitation, the transdermal drug delivery system (TDDS) has emerged as an innovative approach that enables sustained drug release, significantly prolonging the therapeutic duration. Leveraging genetic recombination technology, research teams have ingeniously fused FGF21 with cell-penetrating peptides (CPPs) to construct recombinant FGF21 complexes. These novel conjugates can efficiently penetrate the epidermal barrier and achieve sustained and stable pharmacological activity through TDDS. This review systematically analyzes the potential signaling pathways by which FGF21 accelerates skin wound repair, summarizes the latest advancements in TDDS technology, explores the therapeutic potential of FGF21, and evaluates the efficacy of CPP fusion tags. The manuscript not only proposes an innovative paradigm for the application of FGF21 in skin injury treatment but also provides new insights into its use in transdermal delivery, marking a significant step toward overcoming existing clinical therapeutic challenges. From a clinical medical perspective, this innovative delivery system holds promise for addressing the bioavailability issues of traditional FGF21 therapies, offering new strategies for the clinical treatment of metabolism-related diseases and wound healing. With further research, this technology holds vast potential for clinical applications in hard-to-heal wounds such as diabetic foot ulcers and burns.

Paywalled Paper:

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#24

Here it is proposed that halofuginone, a FDA–approved anti-scleroderma and antiprotozoal drug, is a promising anti-obesity agent acting via FGF-21 and GDF-15 in preclinical mouse and pig models.

The clinical antiprotozoal drug halofuginone promotes weight loss by elevating GDF15 and FGF21

Obesity is a debilitating global pandemic with a huge cost on health care due to it being a major underlying risk factor for several diseases. Therefore, there is an unmet medical need for pharmacological interventions to curb obesity. Here, we report that halofuginone, a Food and Drug Administration–approved anti-scleroderma and antiprotozoal drug, is a promising anti-obesity agent in preclinical mouse and pig models. Halofuginone suppressed food intake, increased energy expenditure, and resulted in weight loss in diet-induced obese mice while also alleviating insulin resistance and hepatic steatosis. Using molecular and pharmacological tools with transcriptomics, we identified that halofuginone increases fibroblast growth factor 21 (FGF21) and growth differentiation factor 15 (GDF15) levels via activating integrated stress response. Using Gdf15 and Fgf21 knockout mice, we show that both hormones are necessary to elicit anti-obesity changes. Together, our study reports the beneficial metabolic effects of halofuginone and underscores its utility in treating obesity and its associated metabolic complications, which merits clinical assessment.

https://www.science.org/doi/10.1126/sciadv.adt3142

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#26

FGF21 is increased by exercise

high carb low protein

https://www.cell.com/cell-metabolism/fulltext/S1550-4131(16)30445-4

FGF21 Expression and Circulation Were Elevated with Low Protein Intakes and Maximal When Low Protein Was Coupled with High Carbohydrate Intakes

and alcohol.

FGF21 and the Physiological Regulation of Macronutrient Preference - PMC.

Finally, it is also relevant that another nutritional intervention was shown to robustly increase FGF21: alcohol consumption. Ample evidence, in both rodents and humans, demonstrates that ethanol intake increases FGF21 production, largely by the liver (123, 164–169). Currently the mechanism through which alcohol drives this effect is not fully clear.

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#27

Aging is associated with increased FGF21 levels but unaltered FGF21 responsiveness in adipose tissue

“Fibroblast growth factor 21 (FGF21) has been proposed to be an antiaging hormone on the basis of experimental studies in rodent models. However, circulating FGF21 levels are increased with aging in rodents and humans. Moreover, despite the metabolic health‐promoting effects of FGF21, the levels of this hormone are increased under conditions such as obesity and diabetes, an apparent incongruity that has been attributed to altered tissue responsiveness to FGF21. Here, we investigated serum FGF21 levels and expression of genes encoding components of the FGF21‐response molecular machinery in adipose tissue from healthy elderly individuals (≥70 years old) and young controls. Serum FGF21 levels were increased in elderly individuals and were positively correlated with insulinemia and HOMA‐IR, indices of mildly deteriorated glucose homeostasis. Levels of β‐Klotho, the coreceptor required for cellular responsiveness to FGF21, were increased in subcutaneous adipose tissue from elderly individuals relative to those from young controls, whereas FGF receptor‐1 levels were unaltered. Moreover, total ERK1/2 protein levels were decreased in elderly individuals in association with an increase in the ERK1/2 phosphorylation ratio relative to young controls. Adipose explants from aged and young mice respond similarly to FGF21 “ex vivo”. Thus, in contrast to what is observed in obesity and diabetes, high levels of FGF21 in healthy aging are not associated with repressed FGF21‐responsiveness machinery in adipose tissue. The lack of evidence for impaired FGF21 responsiveness in adipose tissue establishes a distinction between alterations in the FGF21 endocrine system in aging and chronic metabolic pathologies.”

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#28

High Plasma Level of Fibroblast Growth Factor 21 Is an Independent Predictor of Type 2 Diabetes: A 5.4-year population-based prospective study in Chinese subjects

https://diabetesjournals.org/care/article/34/9/2113/38614/High-Plasma-Level-of-Fibroblast-Growth-Factor-21

“Plasma FGF21 levels were significantly increased in subjects with prediabetes and diabetes and predicted the development of diabetes in humans.”

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#29

FGF21 as Modulator of Metabolism in Health and Disease

" Despite the beneficial action of FGF21 in rodents, the literature in humans is not homogeneous and is supportive of some detrimental effects. For instance, FGF21 serum levels are increased in patients with mutations of mitochondrial DNA in skeletal muscles but not when similar mutations accumulate in other organs. Due to this specificity to mitochondrial myopathies, FGF21 was proposed as a biomarker of mitochondrial dysfunction in skeletal muscles and used as a diagnostic test for these inherited disorders (Suomalainen et al., 2011, p. 21). In other conditions FG21 serum levels have been used as a predictor of disease progression. For instance, higher circulating FGF21 levels were associated with a high mortality rate in end-stage renal disease patients (Kohara et al., 2017). It was also reported in patients with diastolic dysfunction of heart failure who have preserved ejection fraction (Chou et al., 2016), and in those who are serum FGF21 level had been found to be an independent predictor of coronary heart disease (Lee et al., 2017). Moreover, circulating FGF21 levels are elevated in various metabolic disease states, such as obesity, insulin resistance, and type 2 diabetes mellitus (Zhang et al., 2008; Chavez et al., 2009)"

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#30

It would be great to get this FGF21 drug into the ITP for longevity studies! @invivo (perhaps time for another submission!).

Boston Pharmaceuticals to Present State-of-the-Art Lecture and Poster for Once-monthly Efimosfermin Alfa at Digestive Disease Week 2025

Boston Pharmaceuticals, a clinical-stage biopharmaceutical company developing efimosfermin alfa, an investigational, once-monthly FGF21 analogue for the treatment of metabolic dysfunction-associated steatohepatitis (MASH), today announced it will present immunogenicity and biomarker analyses from its Phase 2 study, in participants with stage F2 and F3 fibrosis due to MASH. The results will be presented in a state-of-the-art lecture and poster at Digestive Disease Week (DDW) in San Diego, May 3-6, 2025. These findings further support the advancement of the efimosfermin clinical program to a Phase 3 pivotal study in 2025.

“Efimosfermin has demonstrated rapid and strong response across liver and cardiometabolic biomarkers, along with a favorable safety and tolerability profile. Its once-monthly dosing is expected to be a significant advantage for both prescribers and patients, providing confidence that efimosfermin could set a new standard in MASH treatment,” said Sophie Kornowski, CEO of Boston Pharmaceuticals. “With our robust data, along with the commitment from our Board and a strong funding strategy, we aim to accelerate efimosfermin’s development and begin enrolling patients in a Phase 3 study in F2 and F3 patients before the end of the year, followed by an F4 trial after planned discussions with regulators.”

The state-of-the-art oral presentation will showcase results from the Phase 2, randomized, placebo-controlled, 24-week treatment study in participants with biopsy-confirmed F2 and F3 MASH. The study showed significant improvements in histopathology, with 45.2% (p=0.038) of participants treated with efimosfermin 300mg achieving fibrosis improvement ≥1 stage without worsening of MASH compared to 20.6% in the placebo group, and MASH resolution without worsening of fibrosis in 67.7% of participants (p=0.002) versus 29.4% at 24 weeks. Efimosfermin also demonstrated extrahepatic benefits, including positive impacts on lipids and in participants with diabetes, clinically meaningful improvements in glycemic control. In this study, efimosfermin was generally well-tolerated, with low discontinuation rates due to adverse events, and an overall low incidence of gastrointestinal side effects and injection site reactions. Data to be presented will also highlight the favorable immunogenicity profile of efimosfermin.

Exploratory analyses of the phase 2 study of changes in biomarkers that identify at-risk MASH patients will be presented as a poster. These results strengthen the histopathology findings, demonstrating rapid and marked effects on biomarkers of steatosis, fibrosis, and liver injury, and supports the potential of efimosfermin as a once-monthly, disease-modifying therapeutic for the treatment of MASH.

“These analyses further support the Phase 2 study findings and provides the scientific community with the confidence to advance the development of efimosfermin as a potential therapy for patients with F2 and F3 fibrosis,” said Mazen Noureddin, M.D., M.H.Sc., lead investigator and Professor of Medicine at Houston Methodist Hospital, and Director of the Houston Research Institute. “Based on these encouraging results, we expect to see continued progress as we evaluate findings across histology and non-invasive markers in patients with F2 and F3 MASH receiving efimosfermin treatment for up to 48 weeks.”

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#31

FGF-21, New lease on immunity: UT Health San Antonio scientists discover key component in thymic size, function

Scientists at the University of Texas Health Science Center at San Antonio (UT Health San Antonio) discovered a crucial pathway in the thymus that determines the rate of growth and functional preservation. Surprisingly, this pathway appears to act through both indirect and direct methods. Understanding these functions could help produce treatments that preserve thymic function for longer, boosting the immune system’s power to fight disease.

A UT Health San Antonio-led study, published in Nature Aging in February 2025, highlights the role of the peptide hormone fibroblast growth factor 21 (FGF21) in regulating T-cells and, potentially, preserving thymic size over time. Principal investigator Ann Griffith, PhD, assistant professor in the Department of Microbiology, Immunology and Molecular Genetics, in the Joe R. and Teresa Lozano Long School of Medicine at UT Health San Antonio, said this research could be pivotal in developing a way to preserve strong immune responses across a lifetime.

Paywalled Paper:

Paracrine FGF21 dynamically modulates mTOR signaling to regulate thymus function across the lifespan

https://www.nature.com/articles/s43587-024-00801-1

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#32

Moreover, circulating FGF21 levels are elevated in various metabolic disease states, such as obesity, insulin resistance, and type 2 diabetes mellitus (Zhang et al., 2008; Chavez et al., 2009)"

Follistatin is also increased in metabolic disorders and it has been suggested this is a form of negative feedback, due to its role in inhibiting gluconeogenesis. FGF21 has been shown to inhibit gluconeogenesis in mice, so perhaps this situation is analogous to that of follistatin.

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#33

Paracrine FGF21 dynamically modulates mTOR signaling to regulate thymus function across the lifespan (1).PDF (210.2 KB)

The Griffith lab showed that mTORC1 and mTORC2 in cortical thymic epithelial cells are required for thymic maintenance, which would seem to have implications for rapamycin. Yet a Chinese paper reporting rapamycin-induced thymic atrophy found no changes in cortical TEC numbers — it was the medullary TEC population that declined.

Also, maybe FGF21 is what’s causing the thymic regeneration people are reporting with growth hormone? Perhaps this was obvious already, but I haven’t noticed anyone saying this. There’s a handful of papers linking the two.

A single bolus injection of GH into C57 mice acutely increases both mRNA and protein expression of FGF21 in the liver, thereby leading to a marked elevation of serum FGF21 concentrations. Such a stimulatory effect of GH on hepatic FGF21 production is abrogated by pretreatment of mice with the lipolysis inhibitor niacin. Direct incubation of either liver explants or human HepG2 hepatocytes with GH has no effect on FGF21 expression. On the other hand, FGF21 production in HepG2 cells is significantly induced by incubation with the conditioned medium harvested from GH-treated adipose tissue explants, which contains high concentrations of free fatty acids (FFA). Further analysis shows that FFA released by GH-induced lipolysis stimulates hepatic FGF21 expression by activation of the transcription factor PPARα. Growth Hormone Induces Hepatic Production of Fibroblast Growth Factor 21 through a Mechanism Dependent on Lipolysis in Adipocytes

How about some lipolytic Adderall with your growth hormone to potentiate the FGF21 response? :grin:

chronic administration of GH to normal individuals resulted in a dose-dependent increase in FGF21 levels. IGF-1 levels during GH treatment were supranormal, reaching the range observed in acromegaly 14. There was a dose-dependent increase in NEFAs, and a positive correlation between NEFA and FGF21 levels. As hepatic FGF21 synthesis is influenced by PPARα 6, 7, 18, it has been proposed that GH may increase FGF21 by promoting peripheral lipolysis and increasing NEFAs 9. It has also been suggested that an influence of NEFAs may explain the diurnal changes in FGF21 19. Our dose–response findings would be compatible with this hypothesis, but the concomitantly raised FGF21 and lowered NEFA levels following carbohydrate ingestion argue against the possibility that NEFAs directly regulate FGF21. Accordingly, in our previous human studies of 2-day fasting or consuming a ketogenic diet 8, FGF21 levels were unaltered whereas NEFA levels were markedly increased

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