LongeCityNews Last Updated: 25 March 2026 - 03:14 PM

It has been fifteen years since the first compelling demonstration of clearance of senescent cells in mice. That study paved the way for the transformation of the research community into one convinced of the relevance of cellular senescence to degenerative aging. It also helped to change the culture of aging research more generally, one of the important contributions to a shift in attitudes that has led to a research and development community that understands the treatment of aging as a medical condition to be a practical, desirable goal. Here, discuss the role of cellular senescence in muscle aging specifically; how it contributes to harm and lost function, and what might be done about it.

Cellular senescence is increasingly recognized as a pivotal mechanism driving skeletal muscle aging and the development of sarcopenia, a condition characterized by the progressive loss of muscle mass, strength, and function. This review synthesizes recent evidence detailing the accumulation of senescent cells in aged skeletal muscle, including muscle stem cells (MuSCs), fibro-adipogenic progenitors (FAPs), immune cells, endothelial cells, and even post-mitotic myofibers. Senescence in these cell types impairs regenerative signaling, disrupts niche homeostasis, and propagates chronic inflammation.

Emerging therapeutic strategies, termed senotherapeutics, aim to counteract these effects through senolytics (which eliminate senescent cells) and senomorphics (which modulate the senescence-associated secretory phenotype), as promising interventions to restore muscle function and delay sarcopenia. We will also discuss the remaining challenges and future directions for studying senescence in skeletal muscle.

Link: https://doi.org/10.3803/EnM.2025.2816

There is a reasonable consensus in the research community on the broad categories of issue that lead to and are associated with the aging of the immune system. One can start by dividing immune aging into immunosenescence, a loss of capacity, versus inflammaging, a continual state of unresolved inflammatory signaling, and look at the various contributions to each state, for example. This paper is chiefly interesting for the attempt to propose classes of intervention to address immune aging based on the categorization of issues provided. This would not have been the case twenty years ago; the paper would have outlined what was known of immune aging and possible causes and then stopped. It is a reminder that we now live in an era in which the treatment of aging as a medical condition is widely accepted as an aspirational goal for the life sciences.

Immune aging is best understood not as a collection of isolated defects, but as a complex, interconnected reconfiguration of immune and tissue networks that alters how the body responds to internal and external stressors. Aging causes coordinated changes in innate and adaptive immunity, metabolic pathways, and inter-organ communication, creating a web of interactions whose emergent properties differ fundamentally from those of younger systems. Therapeutic targeting of immune aging aims to rebalance dysregulated inflammatory networks, restore immune adaptability, and improve tissue repair capacity. Current approaches range from mechanistically targeted pharmacological agents to regenerative, metabolic, lifestyle, and precision strategies. Evidence strength varies considerably, with some interventions supported by early clinical data and others remaining primarily experimental.

Interventions directed at fundamental drivers of immune aging, including chronic inflammatory signaling and cellular senescence, represent the most mechanistically advanced therapeutic class. Modulation of the mechanistic target of rapamycin (mTOR) pathway - through agents such as rapamycin and its analogs - has been shown to recalibrate immune metabolism, attenuate excessive inflammatory signaling, mitigate components of the senescence-associated secretory phenotype (SASP), and enhance antiviral responses in older adults, with early-phase clinical trials providing supportive evidence of immunological benefit. However, potential risks include metabolic dysregulation, impaired wound healing, and dose-dependent immunosuppression, emphasizing the need for intermittent or low-dose regimens.

Targeting intracellular inflammatory signaling represents a complementary strategy to rebalance immune network activity. Inhibitors of p38 mitogen-activated protein kinase (p38 MAPK) can restore macrophage functionality, enhance efferocytosis, and promote pro-resolving phenotypes in aging models. While mechanistically attractive, long-term systemic kinase inhibition may carry risks related to host defense impairment and unintended metabolic effects.

Cellular and regenerative interventions aim to restore immune architecture and adaptive capacity. Mesenchymal stem cells (MSCs)-based therapies exhibit immunomodulatory and tissue-repair properties, with encouraging preclinical and early clinical data suggesting benefits for inflammatory dysregulation and impaired regeneration. However, heterogeneity in cell preparations, uncertain durability of effects, and potential tumor-promoting signals remain key concerns. Reconstitution of adaptive immune output through thymic and hematopoietic rejuvenation represents an emerging but strategically important avenue. Beyond IL-7 supplementation, several molecular regulators are under investigation. Forkhead box N1 (FOXN1)-associated pathways, keratinocyte growth factor (KGF), and fibroblast growth factor (FGF) 21 contribute to thymic epithelial integrity and naive T-cell production, with preclinical evidence indicating delayed thymic involution and improved immune function.

Modulation of the gut microbiome through dietary fiber, prebiotics, probiotics, and microbiome-directed therapies can influence systemic inflammation and immune regulation. Diets rich in fiber and prebiotics, targeted probiotic supplementation, and microbiome-directed interventions can enhance gut barrier integrity, promote beneficial microbial taxa, and reduce translocation-induced inflammaging, thereby influencing systemic immune function and inflammatory set points. Improvements in barrier integrity and microbial metabolite production may reduce translocation-driven inflammatory activation. While mechanistically promising and supported by observational studies, variability between individuals and limited standardized clinical trials currently restrict therapeutic generalization.

Link: https://doi.org/10.3390/cells15050414

Myostatin is a circulating inhibitor of muscle growth. It has been an area of research interest for some time, long enough for myostatin loss of function mutants to have been identified or engineered in a range of mammalian species: mice, dogs, cows, and so forth. Complete loss of function in the myostatin gene throughout life is accompanied by exceptional muscle growth and strength, alongside a lesser amount of visceral fat tissue. All told it seems a benefit with little to no downside.

Since muscle mass and strength is lost with advancing age, there have been efforts to develop therapies based on inhibition of myostatin, such as via monoclonal antibodies. The popularity of GLP-1 receptor agonist drugs that produce loss of muscle mass in addition to visceral fat tissue by reducing calorie intake has resulted in an even greater pharmaceutical industry interest in developing ways to avoid this loss of muscle.

There are many possible points of intervention beyond direct inhibition of myostatin expression, circulating levels, or activity. One possibility presently in clinical trials is the inhibition of myostatin receptors. Another example is the upregulation of follistatin, a circulating molecule that acts in opposition to myostatin, and comes with a similar body of work in mouse studies, where genetic engineering or gene therapies have produced heavily muscled mice. A number of therapies claim to improve follistatin levels, and follistatin gene therapies are now used to some degree in the medical tourism industry. Data on human efficacy is thin to non-existent, however.

Meanwhile, research into myostatin continues as the range of possible muscle growth therapies expands. Today's open access paper is a very interesting tour of what can be learned from the very large genetic databases that now exist. Only the one convincing human myostatin mutant with very evident effects is known to the scientific community, but these large databases allow the discovery of other individuals with mutations that produce a weaker loss of function in the myostatin gene. Since genetic data is coupled with a large amount of other health data in the UK Biobank, one can actually map mutation to muscle strength and other characteristics known to be affected by myostatin.

Humans with function-disrupting variants in the myostatin gene (MSTN) have increased skeletal muscle mass and strength, and less adiposity

Myostatin negatively regulates skeletal muscle size in multiple species, and therefore, myostatin blockade has been therapeutically explored to promote muscle growth in humans, including to counter the muscle loss seen in obese humans using GLP1R agonists. In this study, we present results from a large multi-cohort genetic association analysis, using data from 1.1 million individuals to examine the effects of function-disrupting mutations in the myostatin gene (MSTN) on traits relevant to body composition and cardiometabolic health.

Carriers of function-disrupting variants display decreased adiposity, an increase in lean mass, and increased grip strength and creatinine levels. We further characterize the effects of these variants on body composition using whole-body MRI data from UK Biobank, leveraging deep learning models to perform automated image segmentation for 77,572 individuals. Among mutation carriers increased muscle mass is observed across multiple muscle groups, with heterozygote carriers of loss-of-function-like mutations exhibiting increases in excess of 10%.

Our findings demonstrate that lifelong reduction in myostatin function enhances muscle size and strength in humans while decreasing body adiposity, providing insights into the potential benefits and safety of long-term therapeutic blockade of myostatin signaling.

BioAge Labs, Inc. (“BioAge”, “the Company”), a clinical-stage biopharmaceutical company developing therapeutic product candidates for metabolic diseases by targeting the biology of human aging, today provided financial results for the full year ended December 31, 2025 and business updates for the fourth quarter ended December 31, 2025.

“The past few months have been a defining period for BioAge as we delivered positive interim Phase 1 data for BGE-102 demonstrating potential best-in-class reductions in inflammatory biomarkers of cardiovascular risk, including hsCRP, IL-6, and fibrinogen,” said Kristen Fortney, PhD, CEO and co-founder of BioAge. “These results support BGE-102’s potential to deliver injectable-like anti-inflammatory efficacy in a convenient oral therapy, and we are advancing toward a Phase 2a proof-of-concept study in the first half of this year. We also expanded BGE-102 into ophthalmology, where its unique profile positions it as a potential ‘pipeline in a pill’ across cardiovascular, CNS, and ocular diseases. In parallel, we are actively advancing a follow-on NLRP3 inhibitor program to create optionality to address the many diseases driven by the inflammasome. With our upsized $132.3 million follow-on offering, we have further strengthened our balance sheet to support our expanding clinical programs.”

Business Highlights

NLRP3 inhibitor clinical development

• In December 2025, BioAge announced positive interim data from the ongoing Phase 1 single ascending dose (SAD) / multiple ascending dose (MAD) trial of BGE-102, its oral, brain-penetrant NLRP3 inhibitor. BGE-102 was well tolerated across all doses, with dose-proportional pharmacokinetics supporting once-daily dosing, 90–98% suppression of IL-1β in an ex vivo whole blood assay at Day 14, and cerebrospinal fluid concentrations exceeding the IC90 at doses of 60 mg and above — a key differentiator from other NLRP3 inhibitors in development. The Company expanded the trial to include MAD cohorts in participants with obesity and elevated hsCRP.
• In January 2026, BioAge announced additional positive interim Phase 1 data from the first MAD cohort in participants with obesity and elevated hsCRP. At Day 14, BGE-102 120 mg once daily achieved an 86% median reduction in hsCRP, with 93% of participants reaching levels below 2 mg/L, a threshold for reduced cardiovascular risk.
• BGE-102 also achieved a 58% reduction in IL-6 and a 30% reduction in fibrinogen.
• Full Phase 1 data are anticipated in the first half of 2026.
• The Company plans to initiate a Phase 2a proof-of-concept trial in cardiovascular risk in the first half of 2026. The trial has been expanded to incorporate dose-ranging, with the goal of potentially enabling initiation of a Phase 3 registration study by the end of 2027. Phase 2a data are expected in the second half of 2026.

BGE-102 indication expansion into ophthalmology

• BioAge announced the expansion of its BGE-102 development program into ophthalmology, with an initial proof-of-concept study planned in patients with diabetic macular edema (DME). NLRP3 inflammasome activation is a central pathological feature in a range of retinal diseases. In preclinical models, oral BGE-102 demonstrated dose-dependent preservation of retinal vascular integrity, achieving near-complete protection from vascular leakage.
• The Company plans to initiate a Phase 1b/2a proof-of-concept trial in patients with DME in mid-2026, with results anticipated in mid-2027. The DME trial will run in parallel with the BGE-102 Phase 2a cardiovascular risk trial.

APJ agonist program advancement

• The Company continued to advance its oral and parenteral APJ agonist development strategy. Under the exclusive option agreement with JiKang Therapeutics announced in June 2025, BioAge and JiKang are jointly advancing a novel APJ agonist nanobody demonstrating at least 10-fold greater potency than apelin toward Investigational New Drug (IND)-enabling studies.
• In parallel, BioAge is progressing its proprietary portfolio of orally active APJ agonists for which it filed a U.S. provisional patent application in May 2025.
• BioAge intends to file the first IND for an APJ program by 2026 year end.

Upsized follow-on public offering

• In January 2026, BioAge completed an upsized follow-on public offering of 5,897,435 shares of common stock at a public offering price of $19.50 per share, generating gross proceeds of approximately $115.0 million. In February 2026, the underwriters exercised their overallotment option in full, purchasing an additional 884,615 shares of common stock at the public offering price, resulting in total gross proceeds from the offering of approximately $132.3 million. The offering was led by Goldman Sachs, Piper Sandler, and Citigroup. The Company estimates that the proceeds from this financing, together with our $285.1 million in cash, cash equivalents, and marketable securities as of December 31, 2025, will be sufficient to fund operations through 2029 based on its current operating plan.

Strategic partnerships and discovery platform

• BioAge’s multi-year research collaboration with Novartis, focused on discovering novel therapeutic targets at the intersection of aging biology and exercise physiology, continued to advance, with multiple targets under evaluation.
• The Company progressed its strategic collaboration with Lilly ExploR&D for the development of therapeutic antibodies targeting novel metabolic aging targets identified through BioAge’s discovery platform.
• BioAge continued to advance its initiative to comprehensively profile and analyze samples from the HUNT Biobank in Norway through its collaboration with Age Labs AS, generating molecular insights from more than 17,000 individual samples tracking the transition from health to disease over decades of lifespan.

For more information, read the full release here.