Follistatin, Gene Therapy, Muscle Mass, and Longevity

Frailty and Metabolic Syndrome cast gaunt (and flabby) shadows over our aging world; the need for new therapeutics has never been so urgent.

Follistatin gene therapy addresses two pressing epidemics: frailty from sarcopenia (age-related muscle loss) and Metabolic Syndrome — a constellation of issues including insulin insensitivity, hypertension, high cholesterol, and excess body fat (Cornier, 2008).

Heart disease is the leading cause of death in the developed world; aging and Metabolic Syndrome are its primary contributors.

Follistatin gene therapy has been successfully used in patients with muscular dystrophy (Mendel, 2012; Mendel, 2015).

In subjects given epicatechin (a compound that slightly elevates follistatin), marked increases in grip strength were observed. A seemingly crude metric, it is a decent biomarker of general health as well as a predictor of all-cause mortality.

They saw this happen within one week (Guieterez et. al, 2014).

What is Follistatin?

Belgian Blues are yoked.

No, not that kind of yoked — that’s for oxen.

Follistatin removes myostatin, a key constraint on muscle size.

Popular images of “double-muscled” animals don’t all come from a Photoshopper’s fevered imagination.

And no, moderate myostatin inhibition does not produce extreme results.

Proper diet and exercise slow muscle loss, but the aging process, left unchecked, tips the scales in sarcopenia’s favor.

Which is why follistatin gene therapy could soon become as routine as an annual checkup.

Prevention is best, but follistatin offers hope to everyone, including those who might consider themselves too far gone.

Tang and colleagues showed that follistatin gene therapy alleviates metabolic inflammation and arthritis in rats made obese with a high-fat diet (Tang, 2020).

Those who are overweight, underweight, obese, or have otherwise never had an athletic bone (or myocyte) in their body all stand to gain from follistatin.

Multifaceted Benefits

While myostatin inhibition is the main way follistatin encourages muscle growth, it is probably not the only one.

Enhanced muscle growth was even observed in mice born without myostatin (Lee, 2007).

From a longevity standpoint, what’s most interesting are its less visible effects.

Insulin insensitivity and atherosclerotic plaques are topics most of us would prefer to avoid, but like so many other unpleasant subjects, they eventually find us.

Optimal body composition is pivotal factor to maintaining healthy cholesterol levels and staving off hypertension (Butcher, 2018).

High cholesterol, a contributor to atherosclerosis, is a formidable foe. Current interventions, like statin drugs, come with a variety of unwanted side-effects (Ruscica, 2022).

Unfortunately, high cholesterol levels cannot be ignored for long.

Lower levels of muscle mass have been repeatedly linked to an increased risk of atherosclerosis (Ko, 2016; Ochi, 2010).

While some may argue that diet and exercise could be confounding factors, it appears that total muscle mass, in and of itself, offers protection, primarily through its impact on metabolic health.

Ochi’s group concluded that, even after adjusting for these factors, that “low relative muscle mass was associated with an increased prevalence of subclinical coronary artery disease and the degree of CAC [Coronary Artery Calcium] in a dose-dependent manner.”

As a gene therapy that may only require one or two injections in a lifetime, follistatin is a novel preventative measure. It’s one of the most promising ways to stave off issues that can quietly mount for decades before striking as a stroke or heart attack.

The loss of intramuscular fat, one of the benefits of follistatin, triggers a cascade of desirable metabolic changes.

This is not just about achieving a buffer or leaner physique; it’s about enhancing a key part of healthspan.

Best of all, it works even for those with significant genetic disadvantages and those who can’t engage in rigorous exercise.

This is the beauty of myostatin inhibitors.

And there’s more

Like telomerase and Klotho, follistatin is versatile.

To paraphrase da Vinci: everything affects everything, and this is especially true for our bodies.

Most recently follistatin, which is produced in the liver, protects against injury. Liver fibrosis was reduced by 32% in the veritas group. As much as 90% less cell death was observed in the treated mice (Patella, 2006).

Follistatin is integral to bone density as well (Kirk, 2020; Jürimäe, 2023).

And hair…

26 subjects with male pattern baldness experienced significant hair growth and thickening after a single injection of follistatin other growth factors (Zierling, 2011).

And our brains…

Researchers recently discovered a link between Alzheimer’s disease and lean body mass.

With data from the UK Biobank, they studied the relationship between certain genetic variations associated with lean body mass and a person’s risk of developing Alzheimer’s.

Several mechanisms that may explain this protective effect. The most likely, of course, is the known link between Metabolic Syndrome and cognitive dysfunction (Daghlas, 2023; Tahmi, 2021).

This is why BioViva selected follistatin, along with telomerase, as a gene therapy target. Follistatin showed remarkable results when delivered with BioViva’s CMV vector, improving median lifespans in mice by 32.5% (Jaijyan, 2022).

Authored by Adam Alonzi

Adam is a writer, independent researcher, and video maker. He is the Marketing Director for BioViva Science. Visit adamalonzi.com for more.

References and Suggested Reading

Butcher, Joshua T., et al. “Increased muscle mass protects against hypertension and renal injury in obesity.” Journal of the American Heart Association 7.16 (2018): e009358.

Cornier, Marc-Andre, et al. “The metabolic syndrome.” Endocrine reviews 29.7 (2008): 777–822.

Daghlas, Iyas, Malik Nassan, and Dipender Gill. “Genetically proxied lean mass and risk of Alzheimer’s disease: mendelian randomisation study.” BMJ medicine 2.1 (2023).

Jürimäe, Jaak, et al. “Follistatin Is Associated with Bone Mineral Density in Lean Adolescent Girls with Increased Physical Activity.” Children 10.7 (2023): 1226.

Kirk B, Feehan J, Lombardi G, Duque G. Muscle, Bone, and Fat Crosstalk: the Biological Role of Myokines, Osteokines, and Adipokines. Curr Osteoporos Rep. 2020 Aug;18(4):388–400. doi: 10.1007/s11914–020–00599-y. PMID: 32529456.

Gu, Chuansha, et al. “Role of follistatin-like protein 1 in liver diseases.” Experimental Biology and Medicine 248.3 (2023): 193–200.

Gutierrez-Salmean, Gabriela, et al. “Effects of (−)-epicatechin on molecular modulators of skeletal muscle growth and differentiation.” The Journal of nutritional biochemistry 25.1 (2014): 91–94.

Jaijyan DK, Selariu A, Cruz-Cosme R, Tong M, Yang S, Stefa A, Kekich D, Sadoshima J, Herbig U, Tang Q, Church G, Parrish EL, Zhu H. New intranasal and injectable gene therapy for healthy life extension. Proc Natl Acad Sci U S A. 2022 May 17;119(20):e2121499119.

Lee, Se-Jin. “Quadrupling muscle mass in mice by targeting TGF-ß signaling pathways.” PloS one 2.8 (2007): e789.

Morley, John E., et al. “Sarcopenia.” Journal of Laboratory and Clinical Medicine 137.4 (2001): 231–243.

Mendell, Jerry R., et al. “A phase 1/2a follistatin gene therapy trial for becker muscular dystrophy.” Molecular Therapy 23.1 (2015): 192–201.

Mendell, Jerry R., et al. “Gene therapy for muscular dystrophy: lessons learned and path forward.” Neuroscience letters 527.2 (2012): 90–99.

Ko, Byung-Joon, et al. “Relationship between low relative muscle mass and coronary artery calcification in healthy adults.” Arteriosclerosis, thrombosis, and vascular biology 36.5 (2016): 1016–1021.

Ochi, Masayuki, et al. “Arterial stiffness is associated with low thigh muscle mass in middle-aged to elderly men.” Atherosclerosis 212.1 (2010): 327–332.

Patella S, Phillips DJ, Tchongue J, de Kretser DM, Sievert W. Follistatin attenuates early liver fibrosis: effects on hepatic stellate cell activation and hepatocyte apoptosis. Am J Physiol Gastrointest Liver Physiol. 2006 Jan;290(1):G137–44. doi: 10.1152/ajpgi.00080.2005. Epub 2005 Aug 25. PMID: 16123203.

Riley, Lance A., and Karyn A. Esser. “The role of the molecular clock in skeletal muscle and what it is teaching us about muscle-bone crosstalk.” Current osteoporosis reports 15.3 (2017): 222–230.

Ruscica, Massimiliano, et al. “Side effects of statins: from pathophysiology and epidemiology to diagnostic and therapeutic implications.” Cardiovascular Research 118.17 (2022): 3288–3304.

Smith, Rosamund C., and Boris K. Lin. “Myostatin inhibitors as therapies for muscle wasting associated with cancer and other disorders.” Current opinion in supportive and palliative care 7.4 (2013): 352.

Tahmi, Mouna, Priya Palta, and José A. Luchsinger. “Metabolic syndrome and cognitive function.” Current Cardiology Reports 23 (2021): 1–20.

Tang, Ruhang, et al. “Gene therapy for follistatin mitigates systemic metabolic inflammation and post-traumatic arthritis in high-fat diet–induced obesity.” Science Advances 6.19 (2020): eaaz7492.

Ziering, Craig, et al. “Hair Regrowth Following a Wnt-and Follistatin-Containing Treatment: Safety and Efficacy in.” J Drugs Dermatol 10.11 (2011): 1308–1312.