Helen M. Blau | PAS Academician

Enlisting Stem Cells to Regenerate and Rejuvenate Skeletal Muscle by Inhibiting a Gerozyme


Stem cell therapies have the potential to revolutionize the treatment of human diseases by repairing or replacing damaged or aged organs and tissues. Stem cells, the crux of regenerative medicine, are transforming biomedical science. These cells hold tremendous promise for treating a range of diseases (Blau and Daley, 2019). Worldwide, there are many ongoing stem cell-based clinical trials. Stem cell therapies are being used to treat movement disorders like Parkinson’s Disease or to restore sight to those with age-related macular degeneration or corneal abrasions. These examples underscore the remarkable progress that has been made in recent years using stem cell therapies to address some of the most devastating diseases.

Here we discuss a form of regenerative medicine that bypasses the need to isolate, cultivate, propagate, and transplant stem cells into the body. This approach entails stimulating the stem cells present in certain adult tissues and takes advantage of their inherent potential to repair tissue damage in situ. It overcomes complications of cell transplantation arising from immune rejection and is likely to be less costly and labor-intensive. The type of oral small molecule treatment we envision may be a viable strategy for the globalization of regenerative medicine to improve human welfare. In principle, such therapeutics could be developed at relatively low cost, easily disseminated, and readily administered. Clearly, this approach cannot address all of the needs of regenerative medicine; however, for a subset of disorders it poses an exciting alternative to stem cell transplantation. We present an example, our discovery of a gerozyme, a pivotal regulator of muscle aging, that can be inhibited using a small molecule in order to enhance the function of muscle stem cells and myofibers. This therapeutic strategy has the potential to overcome the loss of mobility and strength that plagues the lives of many individuals who suffer from muscle wasting.


On the façade of the Casina Pio IV of the Vatican is a depiction of Aurora, the Goddess of dawn, and Tithonus, the prince of Troy (Figure 1). Aurora fell deeply in love with the mortal Tithonus and wanted to keep him as her lover forever. She pleaded with Jupiter to bestow immortality on Tithonus, and Jupiter granted her wish. However, Aurora had made a grave mistake; she failed to ask for eternal youth. Tithonus continued to age and was destined to live forever as a decrepit old man.

There has long been a quest for a treatment that increases our longevity. However, the quest for treatments that increase quality of life is equally important. Although we are living longer than previous generations, that increase in lifespan is not accompanied by an increase in healthspan. Instead, like Tithonus, for many people these extra years are plagued by age-related chronic illness (Bellantuono, 2018). Enhancing healthspan, or quality of life, is the focus of regenerative medicine. Clinical trials are underway in numerous countries. These studies primarily employ three major stem cell types: embryonic stem cells (ESCs), induced pluripotent stem cells (iPSCs) and adult stem cells (ASCs).

While ESCs have therapeutic potential, they are limited by their availability and by ethical concerns regarding their source (Lo and Parham, 2009). iPSCs, discovered by Nobel Laureate and PAS member Shinya Yamanaka, are pluripotent like ESCs, and obviate destruction of an embryo required for ESC use (Takahashi and Yamanaka, 2006). iPSCs can be generated from any somatic cell. By transiently overexpressing four transcription factors, somatic cells are rendered pluripotent, able to propagate and increase in numbers almost indefinitely, and then differentiated into a range of specialized cell types such as cardiomyocytes and neurons. iPSCs enable in vitro modeling of heritable diseases using patient-derived cells (Yoshida and Yamanaka, 2017), as well as personalized drug screening (Sayed et al., 2016). IPSCs have been differentiated into dopaminergic neurons to correct the movement disorder associated with Parkinson’s Disease following transplantation (Song et al., 2020). In addition, transplanted retinal pigment epithelial cells show promise for restoring sight to individuals with age-related macular degeneration (Mandai et al., 2017).

An alternate source of stem cells are specialized cells, termed adult stem cells (ASCs), that reside in certain tissues of our body, dedicated to the repair of that tissue, and poised to spring into action upon injury (Figure 2). The first to be used clinically were the hematopoietic stem cells (HSCs) resident in the bone marrow, which rescued victims of radiation sickness after World War II and have been used extensively to treat malignant disease (Till and McCulloch, 2011). Notably, the ability to isolate and propagate the self-renewing HSC in vitro still remains an unmet challenge. Other tissue-specific stem cells have met this challenge, for instance skin stem cells, or holoclones, that were isolated from a boy with a congenital mutation that leads to the highly debilitating genetic blistering disease Junctional Epidermolysis Bullosa. The bedridden boy’s stem cells were genetically engineered to express the missing protein and then transplanted to cover most of his body (Mavilio et al., 2006). Because they harbored the stem cell property of self-renewal, this treatment endured (Kueckelhaus et al., 2021), unlike the skin grafts used previously to treat burn victims (Gallico et al., 1984). Following treatment, the boy was able to attend school and even play soccer. Such advances highlight the exciting prospects for stem cell applications in regenerative medicine for improving quality of life.

Discovery of Muscle Stem Cells

In 1961, Mauro’s striking electron microscopy images revealed satellite cells, mononucleated cells juxtaposed to multinucleated myofibers, which he postulated were self-renewing stem cells, present in the body for the purpose of growth and repair (Mauro, 1961). Satellite cells were eventually proven to be bona-fide muscle stem cells (Sacco et al., 2008), and soon after shown to be required for muscle growth and regeneration after injury (Lepper et al., 2011; McCarthy et al., 2011; Murphy et al., 2011; Sambasivan et al., 2011). Satellite cells, now commonly known as muscle stem cells (MuSCs), are a unique model for studying regeneration. MuSCs exist in a quiescent state in their niche until they are activated to self-renew or commit to differentiate, fuse, and develop into myofibers. Each of these steps can be tracked by the expression of a cascade of distinct transcription factors and exploited to study cell fate transitions in depth during development and how these cell fate transitions are recapitulated in regeneration (Porpiglia et al., 2017). MuSCs informed our understanding of stem cell dormancy, or quiescence (Brack and Rando, 2007). Myogenesis set the stage for our understanding of stem cell heterogeneity and the features and role of the stem cell niche in the active maintenance of the stem cell state. Moreover, much has been learned about the molecules that mediate cell fusion essential to forming the multinucleate myofiber syncytium, the transcriptional and epigenetic activation of muscle-specific genes, metabolic reprogramming, and autophagy and mitophagy. These processes, that are essential to muscle growth, differentiation, and maturation, provide a blueprint for other adult stem cell types and how to gain mechanistic insights into their role in regenerating specific tissues (Fuchs and Blau, 2020).

Aging and Muscle Loss

Muscles contribute far more to our lives than strength. They are key to our sense of self and impact our ability to learn and remember, and to build and maintain relationships. Skeletal muscle is one of few organs that can be readily accessed and manipulated. Muscles can be exercised and trained, and that exercise and training directly correlates with increases in muscle size, endurance, and overall performance. Good musculature is also the basis of beauty and an indicator of health. The mind and body are inseparable, consequently few things are as devastating as a loss of mobility.

Humans lose approximately 10% of their muscle mass every decade after age 50. The extreme form of this muscle loss, termed sarcopenia, impacts 5% of people aged 60-70, and 30% of people 80 years of age or older (Figure 3) (Fielding et al., 2011), and is a common complication of cancers (Colloca et al., 2019). This loss of muscle has profound consequences for longevity and quality of life. Sarcopenic adults are frail, unable to perform basic tasks such as rising from a chair, or walking. They are more likely to fall and become injured, leading to dependency and in many cases institutionalization, as well as increased risk of death (Tsekoura et al., 2017). Sarcopenia exerts a huge toll, not only on the patients themselves, but also on their families and communities. Despite its prevalence and impact, the management of sarcopenia is primarily focused on physical therapy for muscle strengthening and gait training. There are currently no pharmacologic agents available for the treatment of muscle atrophy due to disuse after a fall or disease, due to aging, or heritable muscle wasting as in Spinal Muscular Atrophy.

Gerozyme: A Pivotal Regulator of Muscle Wasting in Aging

The Blau laboratory recently formulated the hypothesis that there exists a class of enzymes whose action triggers a gene expression pathway common to a number of tissues in aging, which we termed “gerozymes” (Figure 4). The activity of a gerozyme increases progressively over the lifespan of an organism due to aberrant expression of “gerogenes” that promote aging, similar to the aberrant expression of oncogenes that promote cancer. The Blau group has recently identified the enzyme 15-hydroxyprostaglandin dehydrogenase (15-PGDH), the prostaglandin degrading enzyme, as a gerozyme in muscle. Below I describe how we identified 15-PGDH and describe how it triggers aging-associated changes in stem cell and tissue function. In addition, I describe a method to therapeutically target its activity using a small molecule inhibitor, which leads to increased Prostaglandin E2 (PGE2), which in turn induces muscle regeneration and rejuvenation(Ho et al., 2017; Palla et al., 2021). To our knowledge, 15-PGDH is the first gerozyme to be described.

Combatting Muscle Injury and Muscle Aging

We have discovered that inhibition of the gerozyme, 15-PGDH, remodels aged muscle morphology and augments strength by two complementary mechanisms (Figure 5). Inhibition of the 15-PGDH results in an increase in levels of PGE2, an inflammatory metabolite that we showed is part of the body’s natural healing mechanism. The potency of this treatment derives from its dual function: PGE2 enhances aged muscle stem cell function in regeneration and acts directly on myofibers leading to their rejuvenated form and contractile function (Ho et al., 2017; Palla et al., 2021).

PGE2 signaling is essential for regeneration and strength recovery after injury

Exercise, a form of muscle injury, precipitates a skeletal muscle inflammatory response and activates local resident MuSCs. Diverse immune cell types infiltrate the injured tissue, and there is a sequential release of cytokines and growth factors. We postulated that an inflammatory mediator could serve to activate MuSCs and promote their function in regeneration (Ho et al., 2017). We found that EP4, a G-coupled protein receptor for PGE2, is increased on MuSCs activated by injury and detected a surge in the levels of PGE2 in mouse muscle lysates temporally coincident with the surge in immune cell infiltration (Tidball, 2017). Treatment of MuSCs with PGE2 in culture increased their proliferative capacity and viability through cAMP-mediated activation of the transcription factor Nurr1.

To test whether PGE2 signaling is required for muscle regeneration and strength recovery, we generated a mouse model in which EP4 is specifically and conditionally ablated in MuSCs. Regeneration after muscle injury was impaired, and the young mice did not regain their strength. We analyzed the effects of treatment with a nonsteroidal anti-inflammatory drug (NSAID, like ibuprofen), which is known to block the production of prostaglandins by inhibiting COX-1 and COX-2 enzymes (Schoenfeld, 2012) and again observed a loss of regenerative capacity after muscle injury accompanied by a marked reduction in force (Figure 6). Together, these data show that PGE2 is essential to MuSC expansion and that PGE2 levels act as a rheostat that controls the efficacy of regeneration (Ho et al., 2017).

Aged MuSCs are less regenerative

Regenerative capacity declines with aging, although MuSC numbers remain relatively constant, indicating that a paucity of MuSCs is not the root cause of impaired regeneration (Brack and Rando, 2007). Instead, a subset of the aged MuSCs becomes dysfunctional, and is less able to proliferate and engraft (Cosgrove et al., 2014; Porpiglia et al., 2022). This impairment of regenerative function is further exacerbated by age-associated changes to the MuSC niche and systemic changes in the aging organism (Conboy et al., 2005; Gopinath et al., 2014). Data from my lab showed that the reduced function of aged MuSCs can be overcome in culture by the combined effects of a small molecule inhibitor of p38α/β MAPK and a hydrogel substrate with biophysical properties matching the soft elasticity of healthy young muscle tissue. These biochemical and biophysical cues synergize to stimulate the rapid expansion of functional aged stem cells to generate a MuSC population with rejuvenated function capable of restoring strength to injured aged muscles (Blau et al., 2015; Cosgrove et al., 2014; Gilbert et al., 2010).

15-PGDH is a Gerozyme: a pivotal molecular regulator of muscle aging and rejuvenation

During aging, skeletal muscles undergo detrimental structural and functional changes. The loss of function with aging arises from disrupted cell-cell interactions and aberrant cell signaling pathways, particularly those related to protein turnover, and mitochondrial function (Cohen et al., 2015; Frenk and Houseley, 2018; Lee et al., 2007; Lenk et al., 2010). We investigated the role of PGE2 in muscle atrophy and found by mass-spectroscopy that PGE2 declines and that the prostaglandin degrading enzyme, 15-PGDH, increases with aging and is the driver of that decline in aged muscles (Palla et al., 2021). We therefore postulated that 15-PGDH is a gerozyme, a pivotal molecular determinant of muscle aging. To fit the definition of a gerozyme, (i) inhibiting its activity should rejuvenate aged muscles and (ii) increasing its activity should cause young muscles to prematurely age.

We first tested this hypothesis by decreasing enzyme levels in aged mice via a localized intramuscular AAV9-sh15-PGDH gene therapy approach. We observed the expected significant reduction in 15-PGDH mRNA levels, protein levels, and specific activity coupled with an increase in PGE2 levels. We noted that depleting 15-PGDH led to a marked increase in cross-sectional myofiber area and a significant increase in both muscle mass and muscle force after only one month of treatment (Palla et al., 2021). Using a small molecule inhibitor of 15-PGDH (SW), we observed a similar 2-fold increase in PGE2 levels in aged mice, on par with PGE2 levels in young mice. Importantly, inhibition of 15-PGDH activity with SW promoted muscle hypertrophy and augmented both strength and endurance of aged mice. Thus, 15-PGDH met the first requirement of a gerozyme.

To address the second requirement of a gerozyme, we tested if ectopic expression of 15-PGDH suffices to cause aging of young muscle. We used an AAV9-mediated gene therapy approach to deliver 15-PGDH to the muscles of young adult mice. Mass spectroscopy revealed the expected marked decline in PGE2 and PGD2 levels in young muscles expressing 15-PGDH, similar to that observed in aged muscles. In addition, the average cross-sectional area of individual myofibers was diminished, muscle mass decreased, and force markedly declined in young adult mice. Importantly, aberrant expression of 15-PGDH in young muscle triggered changes in aging associated gene expression: increases in the expression of known markers of muscle atrophy, including atrogenes Trim63 (MuRF1) and Fbxo32 (Atrogin-1) (Milan et al., 2015; Sandri et al., 2004; Stitt et al., 2004) (Palla et al., 2021). Given the pleiotropic nature of aging, the dramatic induction of atrophy and muscle wasting caused by a relatively moderate increase in the activity of a single enzyme was both unexpected and striking. These experiments identify 15-PGDH as a gerozyme.

Identification of the cellular source of the gerozyme in aged mouse muscles

To understand how 15-PGDH exerts its deleterious effects we capitalized on an imaging technique known as (CODEX, CO-Detection by indEXing) to visualize simultaneously 40 cell-specific markers including 15-PGDH in young and aged muscle tissue sections. CODEX is a multiplexed tissue imaging technology that uses antibodies conjugated with unique DNA barcodes that are iteratively rendered visible by cycles of hybridization and chemical denaturation with fluorophore-conjugated complementary DNA probes(Black et al., 2021; Schürch et al., 2020). 15-PGDH was detected at significant levels in aged myofibers, as well as in interstitial cells, in particular CD11b+ and CD45+ macrophages, a finding confirmed by RNAseq. These results implicate both autocrine (via myofibers) and paracrine (via macrophages) PGE2 regulatory mechanisms that drive aging-associated changes in skeletal muscle function(Palla et al., 2021; Wang et al., 2022).

Rejuvenated muscle gene expression and morphology following gerozyme inhibition

A transcriptome analysis revealed a decline in deleterious signaling pathways linked to age-related muscle atrophy, particularly in protein degradation pathways and TGFβ signaling following one month of gerozyme inhibition. (Palla et al., 2021).

Strikingly, we observed a strong enrichment of mitochondrial pathways, including mitochondrial oxidative phosphorylation, ATP synthesis and other metabolic and energy generating functions in the aged muscle tissue transcriptome after SW treatment. SW increased the expression of components of all mitochondrial electron transport chain complexes. Additionally, mRNA levels of the master regulator for mitochondrial biogenesis peroxisome proliferator-activated receptor gamma coactivator 1-alpha (Pgc1α) was restored to youthful levels. SW also increased overall mitochondrial content, and key measures of mitochondrial function such as citrate synthase and succinate dehydrogenase activity and increased mitochondrial membrane potential.

Most strikingly, transmission electron microscopic (TEM) images revealed that SW treatment led to a remarkable remodeling of the aged muscle tissue, restored aged mitochondria to a compact circular morphology resembling that seen in young, and increased overall mitochondrial abundance. In addition, myofibril widths increased, consistent with the increase in cross-sectional area and muscle mass (Figure 7). These images, of which thousands were quantified, provided evidence that a short-term drug treatment can lead to a remarkable tissue rejuvenation (Palla et al., 2021).


We have established the prostaglandin degrading enzyme, 15-PGDH, as a skeletal muscle gerozyme - an enzyme that is a pivotal molecular regulator of muscle aging (Figure 8). Since 15-PGDH is also elevated in aged human muscles, we postulate that it plays a similar role in human muscle wasting. Because 15-PGDH is elevated in several tissues in aged individuals, it is possible that it has a broader role as a gerozyme in a range of tissues. Our research highlights the potency of the gerozyme, 15-PGDH, as a ‘master regulator of muscle aging’. If expressed in young muscles, it causes premature muscle wasting similar to aging. Additionally, its deleterious effects in aged muscles can be surmounted leading to a rejuvenated tissue, with augmented function and the potential to increase quality of life.

Progress in regenerative medicine has been remarkable and the potential to treat some of the most intractable diseases is becoming a reality. Methods for stem cell production and delivery will become more stream-lined and costs for stem cell therapies will certainly decrease making them more universally available. Here we present an alternative strategy. This approach capitalizes on activating adult stem cells, that are naturally present in many of our body’s tissues, to regenerate function lost due to injury, heritable diseases, or aging. If the small molecule 15-PGDH inhibitor described here can be generated at low cost and in an oral formulation, it may be possible to disseminate it more broadly, setting the stage for other therapeutics to meet a need for more global therapeutics.


We wish especially to thank Andrew T. V. Ho, PhD for the illustrations and Gabriella C. Marino for introducing me to the Aurora myth and its depiction on the façade of the Casino Pio IV of the Vatican. We also thank the talented group of multi-disciplinary international scientists in my lab for their seminal contributions in charting new territory. We are grateful to The Baxter Foundation, the Li Ka Shing Foundation, and the National Institutes of Health (AG069858, AG020961) for support.


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