LongeCityNews Last Updated: 09 January 2026 - 07:40 PM

By inhibiting the aging-related enzyme 15-PGDH, scientists have shifted cartilage cells towards a healthier phenotype, leading to a significant improvement in a mouse model of osteoarthritis [1].

The hard-to-repair part

Articular cartilage (the smooth, load-bearing cartilage on the ends of bones) doesn’t repair well with age or after injury [2], which is why osteoarthritis is hard to treat. This disease affects 1 in 5 adults, leading to reduced quality of life for 33 million patients in the US alone. Current treatments primarily focus on pain relief and joint replacement, with no approved therapies targeting the cartilage loss that causes osteoarthritis.

Previous research has shown that 15-hydroxyprostaglandin dehydrogenase (15-PGDH) increases with age in multiple tissues and can blunt regeneration by degrading key prostaglandins, lipid signaling molecules that influence inflammation and tissue repair. In those earlier models, which studied muscle, nerve, bone, and blood, inhibition of 15-PGDH boosted endogenous prostaglandin signaling and improved tissue repair [3].

Since osteoarthritis is fundamentally a problem of failed repair in articular cartilage, and cartilage regeneration strategies based on endogenous repair have been limited, a team led by researchers from Stanford Medicine decided to investigate the role of 15-PGDH in aged and injured cartilage. Their study was published in the journal Science.

More healthy cartilage

Using immunohistochemistry on knee joints from young (4 months) and aged (24 months) mice, the team discovered that cells expressing 15-PGDH were present in multiple joint tissues. In cartilage specifically, 15-PGDH abundance was about twice as high in aged mice. Aged knee joints had much thinner cartilage and multiple breaks in the cartilage surface.

A cohort of aged male mice was treated daily intraperitoneally with a small molecule 15-PGDH inhibitor (PGDHi) for one month. As a result, the knee joints of PGDHi-treated aged mice showed increased cartilage thickness and uniformness, almost on par with young mice.

The “extra” cartilage in treated aged mice was not fibrous and rough, as often happens after an injury heals, but bore many signs of normal cartilage, with increased expression of type II collagen (COL-2) and aggrecan (ACAN), the main structural building blocks of healthy cartilage, and of lubricin (PRG4), a surface lubricant that helps cartilage glide with low friction.

Safranin O staining: red/orange marks proteoglycan-rich cartilage matrix (healthier cartilage); fading indicates cartilage matrix depletion.

The researchers then wanted to know whether local joint delivery is sufficient in an injury-driven osteoarthritis model. Three-month-old male mice were treated with a series of intra-articular injections of PGDHi starting one week after injury, twice a week for two weeks.

The response was similar to what the team had seen with systemic administration: improved cartilage quality, higher COL-2, and increased aggrecan/lubricin. Pain responses were also better in treated mice: PGDHi-injected mice looked closer to uninjured controls across gait and mechanical pain measures. This particular experiment is relevant to young people as well: even after a successful repair, half of the people who suffer an ACL tear develop osteoarthritis in the injured joint within about 15 years.

No stem cells involved

Tissue regeneration often involves proliferation and differentiation of stem cells, but such cells in cartilage have rarely been seen, which might be a reason why cartilage regenerates poorly. The team made an exciting discovery: the regeneration they had witnessed was mostly due to gene expression changes in existing differentiated cartilage cells rather than a result of stem cell expansion.

The researchers identified multiple chondrocyte clusters in aged cartilage and described three that shift with PGDHi. Hypertrophic chondrocytes, the type that drives cartilage ossification, showed high expression of 15-PGDH. The treatment lowered the abundance of this subtype from 8% to 3%. Another largely harmful subset, fibro-chondrocytes, shifted from 16% down to 8% in the presence of PGDHi.

Conversely, the healthy subtype that actively maintains the extracellular matrix increased in prevalence from 22% to 42%. There was no evidence of drastically increased cellular division, supporting the idea that the positive effect mostly came from the existing cells shifting their behavior.

To make their findings more relevant to humans, the researchers studied samples from 11 osteoarthritis patients undergoing knee replacement and found signs of increased 15-PGDH expression and lower prostaglandin levels. Finally, they treated human cartilage with PGDHi in vitro and saw results similar to those in mice, with increased stiffness pointing to healthy load-bearing behavior.

“This is a new way of regenerating adult tissue, and it has significant clinical promise for treating arthritis due to aging or injury,” said Helen Blau, PhD, professor of microbiology and immunology and a senior author on the study. “We were looking for stem cells, but they are clearly not involved. We are very excited about this potential breakthrough. Imagine regrowing existing cartilage and avoiding joint replacement.”

“Millions of people suffer from joint pain and swelling as they age,” added Nidhi Bhutani, PhD, associate professor of orthopedic surgery, and another senior author. “It is a huge unmet medical need. Until now, there has been no drug that directly treats the cause of cartilage loss. But this [PGDH] inhibitor causes a dramatic regeneration of cartilage beyond that reported in response to any other drug or intervention. Cartilage regeneration to such an extent in aged mice took us by surprise. The effect was remarkable.”

Literature

[1] Singla, M., Wang, Y. X., Monti, E., Bedi, Y., Agarwal, P., Su, S., … & Bhutani, N. (2025). Inhibition of 15-hydroxy prostaglandin dehydrogenase promotes cartilage regeneration. Science, eadx6649.

[2] Hu H, et al. “Endogenous Repair and Regeneration of Injured Articular Cartilage: A Challenging Balance.” Cells. 2021.

[3] Palla, A. R., Ravichandran, M., Wang, Y. X., Alexandrova, L., Yang, A. V., Kraft, P., … & Blau, H. M. (2021). Inhibition of prostaglandin-degrading enzyme 15-PGDH rejuvenates aged muscle mass and strength. Science, 371(6528), eabc8059.

Exercise and physical fitness has been shown to reduce the predicted biological age generated by various epigenetic clocks. Researchers here provide evidence for some of this effect to be mediated by a reduction in inflammatory signaling, also well known as an outcome of exercise and physical fitness. Chronic inflammation is harmful to tissue structure and function, and is also a feature of aging and age-related disease. To the degree that long-term inflammatory signaling unrelated to injury and infection can be minimized, the results should be improved health and modestly slowed aging.

Physical activity (PA) is recognized as a cornerstone of healthy aging, yet the molecular mechanisms linking PA to biological aging remain poorly understood. DNA methylation (DNAm)-based biological aging indicators, such as PhenoAge, provide a means to assess the relationship between PA and aging at the molecular level.

β2-microglobulin (β2M) is elevated in states of chronic inflammation and is implicated in immune senescence. Elevated levels are detected in the plasma and cerebrospinal fluid of aged mice and older adults. This study analyzed data from 936 participants in the U.S. population, assessing associations between PA, β2M levels, and PhenoAge.

Our study showed that increased PA was significantly associated with lower β2M levels, and mediation analysis revealed that reductions in β2M explained 37.67% of the association between PA and PhenoAge. These results align with findings that PA mitigates inflammation by reducing pro-inflammatory cytokines and improving immune function. Importantly, the direct effect of PA on PhenoAge remained significant even after accounting for β2M, suggesting additional pathways through which PA exerts anti-aging effects, such as epigenetic regulation or mitochondrial function.

Link: https://doi.org/10.1016/j.jare.2025.11.047

Retro Biosciences was one of the more comprehensively funded companies in the longevity industry at launch, and has pursued a number of different programs. The first program to reach an initial clinical trial is a small molecule drug to upregulate autophagy, a goal pursued by a wide range of programs, most notably those focused on mTOR inhibitors and related calorie restriction mimetics. Increased autophagy should modestly slow aging, though as always the size of the effect is a guess until human data emerges - and that might take a while. Rapamycin upregulates autophagy, has long been known to do that, costs little, and we still have no idea what it does to the pace of aging in humans.

Longevity biotech Retro Biosciences has achieved its goal of becoming a clinical-stage company in 2025, after dosing the first participant in a clinical trial of its autophagy-focused drug candidate. Retro's clinical drug candidate, RTR242, is a small-molecule therapy designed to restore lysosomal function, a core component of autophagy - our cells' waste-handling and recycling system. In healthy, younger cells, lysosomes maintain an acidic environment that allows the autophagy process to break down damaged proteins and cellular debris. As people age, and particularly in neurodegenerative diseases such as Alzheimer's, lysosomes lose acidity and efficiency. The result is a buildup of toxic protein aggregates that place chronic stress on neurons and contribute to their dysfunction and eventual loss. Retro's approach aims to repair this decline at its source, reactivating the cell's own cleanup machinery rather than targeting the problem downstream.

The Phase 1 study is a randomized, double-blind, placebo-controlled trial in healthy volunteers, conducted at a specialized early-phase clinical unit in Australia. In addition to standard safety and tolerability measures, the study includes exploratory biomarkers tied to autophagy and lysosomal biology, giving Retro its first opportunity to observe whether its mechanistic hypotheses translate into measurable biological signals in humans. Failures in cellular clearance are a common feature across many degenerative conditions, so if the biology proves tractable in humans, the hope is that the approach could have applications beyond neurodegeneration, informing approaches to other disorders where accumulated cellular damage plays a central role.

Link: https://longevity.technology/news/retro-bio-commences-first-in-human-trial/

As you may know, there are significant differences in incidence and outcomes of Alzheimer's disease between the sexes. In research, differences of this nature can help in developing a better understanding of which mechanisms are more versus less important in the disease process, and so guide efforts to produce therapies. The biochemistry of the brain is enormously complex, and thus so is the pathology of Alzheimer's disease. It remains the case that decades of research cannot do any better than practical experimentation when it comes to determining which mechanisms cause the most harm. See the present focus on clearance of amyloid-β aggregates from the brain, for example. Only once the necessary immunotherapies existed could the research community determine that amyloid-β aggregates are not as important as hoped in the pathology of the condition.

The focus of today's open access paper is largely the role of inflammatory, dysfunctional microglia in Alzheimer's disease, and whether this provides a sizable contribution to sex differences in disease outcomes. The role of microglia in Alzheimer's disease is a growing area of research interest that seems likely to lead to novel therapies and initial clinical trials in the years ahead. Microglia are innate immune cells of the central nervous system, somewhat analogous to the macrophages found elsewhere in the body. In addition to attacking pathogens and destroying unwanted cells, they are also involved in regeneration and maintenance of nervous system tissue, including some of the changes to neural circuits needed for learning and memory. When microglia become overly inflammatory, it is harmful to the structure and function of the brain.

Microglial interferon signaling and Aβ plaque pathology are enhanced in female 5xFAD Alzheimer's disease mice, independent of estrous cycle stage

Alzheimer's disease (AD) presents with a sex bias in which women are at higher risk and exhibit more rapid cognitive decline and brain atrophy compared to men. Microglia play a significant role in the pathogenesis and progression of AD and have been shown to be sexually differentiated in health and disease. Whether and how microglia contribute to the sex differences in AD remains to be elucidated. Herein, we characterized the sex differences in amyloid-beta (Aβ) plaque pathology and microglia-plaque interaction using the 5xFAD mouse model and revealed microglial transcriptomic changes that occur in females and males.

Despite women with symptomatic late-onset AD being in the post-menopausal stage, metabolic and pathological changes are seen prior to menopause. For this reason, and because Aβ pathology develops decades prior to clinical presentation, we focused on two hormonally distinct stages of the female rodent estrous cycle (proestrus and diestrus). Our results showed that Aβ plaque morphology is sexually distinct, with females having greater plaque volume and lower plaque compaction compared to males of the same age. Neuritic dystrophy was also increased in female 5xFAD mice, independent of estrous cycle stage. While microglia transcriptomes were not overtly different at the proestrus or diestrus stages, female 5xFAD microglia upregulated genes involved in glycolytic metabolism, antigen presentation, disease-associated microglia, and microglia neurodegenerative phenotype compared to males, some of which have been previously reported.

In addition, we found a novel female-specific enhancement of IFN signaling in microglia, as evidenced by a striking proportion of differentially expressed type 1 interferon genes characteristic of interferon-responsive microglia (IRM). Finally, we validated our transcriptomic results at the protein level and observed that female 5xFAD mice had an enrichment in Aβ+ IRMs compared to males. Collectively, we show that there are sex-specific alterations in Aβ plaque morphology and that endogenous hormonal fluctuations across the estrous cycle do not overtly affect Aβ pathology or microglial transcriptomic profiles. Furthermore, our study identifies a novel sex-specific enhancement of interferon signaling in female microglia responding to Aβ, which may constitute a new therapeutic target for personalized medicine in AD.