Fibroblast growth factor 21 (FGF21) and Longevity

In the Longevity Summit presentations Eric Verdin highlighted FGF21 as a compound that is showing good results in early longevity testing (as much as 36% Lifespan improvement, though Matt Kaeberlein suggests these calculations are based on shorter-lived control mice, and a small number of studies so far):

(Click on image below to enlarge it)

A news report suggests a biotech company is developing an analog that is progressing through trials:

Another company trying to make its mark in Nash is 89Bio with pegozafermin, an FGF21 analogue. The 216-patient phase 2b Enliven study is again in biopsy-confirmed Nash patients with stage F2/3 fibrosis. Three doses of pegozafermin, administered by subcutaneous injection, will be tested against placebo.

The co-primary endpoints are the proportion of participants with histological resolution of Nash without worsening of fibrosis, and with a one-stage or greater decrease in fibrosis stage with no worsening of Nash at 24 weeks.

Akero’s efruxifermin, also a subcutaneous FGF21 analogue, reported a hit in phase 2 in September, but the primary endpoint analysis was flattered by the exclusion of the handful of patients who dropped out of the trial.

Source: Resources | Evaluate

The problem with pegazofermin, however, is that Akero Therapeutics’ (AKRO) efruxifermin and Bristol Myers Squibb’s (BMY) Pegbelfermin are also FGF21 analogs. Pegbelfermin failed a mid-stage trial and BMY shelved the asset, while Akero posted strongly positive data from EFX this September.

More information: 89Bio Stock: Let's Not Give Up Already (NASDAQ:ETNB) | Seeking Alpha

Background Reading on FGF-21

FGF21 Summary

FGF21-Cognitive-Vitality-For-Researchers.pdf (335.4 KB)

j.arr.2017.05.pdf (638.9 KB)

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There is an interesting discussion regarding the FGF-21 research in this video below here starting just after the five minute mark, the video is pre-set to go to this spot below:

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There are just so many compounds that extend the lifespan of mice. Maybe mice aren’t that good of a predictor.

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I look at it a little differently. Lots of compounds extend life in mice in small, independent studies. But very few seem to succeed in larger, more rigorous multi-center studies like the NIA ITP studies.

So my take is to be careful about overinterpreting mouse studies with small N.

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I see more and more research on FGF21 and it continues to be very interesting…

Hormone called FGF21 speeds recovery from alcohol poisoning in mice, has potential to save countless lives, researchers say.

Dallas – A shot of a liver-produced hormone called FGF21 sobered up mice that had passed out from alcohol, allowing them to regain consciousness and coordination much faster than those that didn’t receive this treatment, UT Southwestern researchers report in a new study. The findings, published in Cell Metabolism, could lead to effective treatments for acute alcohol intoxication, which is responsible for about 1 million emergency room visits in the U.S. each year.

As part of this latest study, the researchers delivered enough alcohol to mice to render them unconscious, mimicking a binge drinking session. They then injected some of the animals with FGF21. While those that didn’t receive this agent took about three hours to regain consciousness and stand upright, those that received FGF21 were able to accomplish this feat in half the time.

When the researchers delivered smaller amounts of alcohol more akin to typical human drinking – enough to significantly affect the animals’ coordination – the mice that received FGF21 injections also regained their coordination much faster than those that didn’t receive the hormone.

Further investigations showed that FGF21 acts on noradrenergic neurons, a type of nerve cell in the brain that promotes wakefulness. The hormone didn’t affect alcohol metabolism, though, as both treated and untreated mice showed the same blood alcohol concentrations.

FGF21 appears to specifically affect intoxication from alcohol, Dr. Kliewer said. Animals that received other types of sedatives did not become alert any faster than usual when given this hormone.

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I see a lot of ongoing research on FGF21, it seems to be something we continue to want to track:

FGF21 Has a Sex-Specific Role in Calorie-Restriction-Induced Beiging of White Adipose Tissue in Mice

Calorie restriction (CR) promotes healthspan and extends the lifespan of diverse organisms, including mice, and there is intense interest in understanding the molecular mechanisms by which CR functions. Some studies have demonstrated that CR induces fibroblast growth factor 21 (FGF21), a hormone that regulates energy balance and that when overexpressed, promotes metabolic health and longevity in mice, but the role of FGF21 in the response to CR has not been fully investigated. We directly examined the role of FGF21 in the physiological and metabolic response to a CR diet by feeding Fgf21 -/- and wild-type control mice either an ad libitum diet or a 30% CR diet for 15 weeks. Here, we find that FGF21 is largely dispensable for CR-induced improvements in body composition and energy balance, but that the lack of Fgf21 blunts CR-induced changes in glucose regulation and insulin sensitivity in females. Surprisingly, despite not affecting CR-induced changes in energy expenditure, loss of Fgf21 significantly blunts CR-induced beiging of white adipose tissue (WAT) in male but not female mice. Our results shed new light on the molecular mechanisms involved in the beneficial effects of a CR diet, clarify that FGF21 is largely dispensable

Full Paper:

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Exercise increases serum fibroblast growth factor 21 (FGF21) levels

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Use of FGF21 analogs for the treatment of metabolic disorders: a systematic review and meta-analysis

FGF21 is a hormone produced primarily by the liver with several metabolic functions, such as induction of heat production, control of glucose homeostasis, and regulation of blood lipid levels. Due to these actions, several laboratories have developed FGF21 analogs to treat patients with metabolic disorders such as obesity and diabetes. Here, we performed a systematic review and meta-analysis of randomized controlled trials that used FGF21 analogs and analyzed metabolic outcomes. Our search yielded 236 articles, and we included eight randomized clinical trials in the meta-analysis. The use of FGF21 analogs exhibited no effect on fasting blood glucose, glycated hemoglobin, HOMA index, blood free fatty acids or systolic blood pressure. However, the treatment significantly reduced fasting insulinemia, body weight and total cholesterolemia. None of the included studies were at high risk of bias. The quality of the evidence ranged from moderate to very low, especially due to imprecision and indirection issues. These results indicate that FGF21 analogs can potentially treat metabolic syndrome. However, more clinical trials are needed to increase the quality of evidence and confirm the effects seen thus far.

Open access paper:

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Injection of a hormone called FGF21 rapidly revives intoxicated mice.

A new study shows that a shot of FGF21—a hormone that regulates metabolic pathways—gets intoxicated mice up and running twice as fast as animals that are allowed to come around on their own.

What’s more, mice lacking FGF21 drink more—and take longer to recover from alcohol’s effects—than their hormonally competent counterparts. The findings appear in the journal Cell Metabolism.

Steve Kliewer: The genesis of this particular project was the finding from several laboratories that this particular hormone that we work on, FGF21, is induced dramatically by ethanol. We wanted to know: "What does FGF21 do acutely in terms of ethanol response to ethanol?”

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So, I have to wonder if this drug efruxifermin (EFX), an FGF21 memetic, might provide the longevity benefits that FGF-21 has provided in mouse studies… unfortunately its an injection drug, so the NIA ITP won’t be testing it… but a lab should (or perhaps a Robust Mouse Rejuvenation add-on.)

Akero reports positive results for diabetes-related liver treatment

SOUTH SAN FRANCISCO - Akero Therapeutics, Inc. (NASDAQ:AKRO), a clinical-stage biotechnology company, has published a study indicating that its drug efruxifermin (EFX), when combined with GLP-1 receptor agonist therapy, shows promise in treating liver issues in patients with Type 2 diabetes.

The results, which appeared in Clinical Gastroenterology and Hepatology, come from a subset of the Phase 2b SYMMETRY study and suggest that EFX could be a significant treatment option for metabolic dysfunction-associated steatohepatitis (MASH), previously known as NASH.

EFX is a Fc-FGF21 fusion protein designed to mimic the activity of the native hormone FGF21, which plays a role in regulating metabolism and reducing cellular stress. The treatment has the potential to address the multifaceted nature of MASH by reducing liver fat and inflammation, reversing fibrosis, and improving insulin sensitivity and lipid metabolism.

Company Website:

Related clinical trial:

https://clinicaltrials.gov/study/NCT03976401

Related Reading:

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While we’re waiting for a drug I saw a couple of videos on boosting fgf21 with lifestyle interventions:

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89bio’s MASH Drug Begins Phase III, Aiming to Stand Out in Growing Field

Pegozafermin, an FGF21 analog, to be assessed in two-trial program evaluating weekly, biweekly doses

Pegozafermin is an engineered glycoPEGylated analog of fibroblast growth factor 21 (FGF21) that 89bio is developing as a treatment for MASH as well as severe hypertriglyceridemia (SHTG), where it is under study in the ongoing Phase III Entrust trial (NCT05852431). FGF21 is an endogenous hormone that regulates energy expenditure, glucose, and lipid metabolism.

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FGF21 analog drugs are on the pathway to approval…

Source: NASH field celebrates ‘hurrah moment’ with a first FDA drug approval for the liver disease

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A new paper on FGF-21

Fibroblast growth factor 21 enhances learning and memory performance in mice by regulating hippocampal L-lactate homeostasis

Fibroblast growth factor 21 (FGF21) is one endogenous metabolic molecule that functions as a regulator in glucose and lipid homeostasis. However, the effect of FGF21 on L-lactate homeostasis and its mechanism remains unclear until now. Forty-five Six-week-old male C57BL/6 mice were divided into three groups: control, L-lactate, and FGF21 (1.5 mg/kg) groups. At the end of the treatment, nuclear magnetic resonance-based metabolomics, and key proteins related to L-lactate homeostasis were determined respectively to evaluate the efficacy of FGF21 and its mechanisms. The results showed that, compared to the vehicle group, the L-lactate-treated mice displayed learning and memory performance impairments, as well as reduced hippocampal ATP and NADH levels, but increased oxidative stress, mitochondrial dysfunction, and apoptosis, which suggesting inhibited L-lactate-pyruvate conversion in the brain. Conversely, FGF21 treatment ameliorated the L-lactate accumulation state, accompanied by restoration of the learning and memory defects, indicating enhanced L-lactate uptake and utilization in hippocampal neurons. We demonstrated that maintaining constant L-lactate-pyruvate flux is essential for preserving neuronal bioenergetic and redox levels. FGF21 contributed to preparing the brain for situations of high availability of L-lactate, thus preventing neuronal vulnerability in metabolic reprogramming.

Paywalled Paper:

https://www.sciencedirect.com/science/article/abs/pii/S014181302403472X

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