LongeCityNews Last Updated: 10 January 2026 - 07:50 PM

Disruption of the regulation of circadian rhythms is a known feature of aging. As for everything to do with our biochemistry, this disruption of the circadian clock is complicated. As a starting point, there isn't just one clock. The brain runs clocks, the periphery runs more clocks, and they coordinate with one another via signaling. That coordination breaks down with age, because everything breaks down with age in one way or another, as damage and dysfunction accumulates. We can also discuss whether the various clock mechanisms that sense aspects of the environment function correctly in later life, whether the appropriate signaling is still generated in the right way, whether the receptors for those signals still operate correctly to generate the appropriate cell and tissue responses, and so forth. There are many points at which normal function can be eroded as damage mounts - and it clearly is eroded in the old.

Today's open access paper presents a novel way of looking at how the disruption of the circadian clock may contribute to age-related disease, specifically the risk of neurodegenerative disease in this case. The researchers used study data on movement and heart activity to characterize individual variations in the resilience of the circadian clock to alterations in the environment. An older person who is more affected by the environment is said to have a weak clock, whereas one who is less affected by changes in the environment has a strong clock. A strong clock correlates with a lower risk of dementia. This says little about causation, of course. The same accumulating cell and tissue damage of aging may provoke weakness in the circadian clock at the same time as it contributes to neurodegeneration. That weak clocks correlate with risk of dementia may just be pointing out that people with a greater burden of damage are more impacted than those with less of a burden of damage.

Do our body clocks influence our risk of dementia?

Circadian rhythm is the body's internal clock. It regulates the 24-hour sleep-wake cycle and other body processes like hormones, digestion, and body temperature. It is guided by the brain and influenced by light exposure. With a strong circadian rhythm, the body clock aligns well with the 24-hour day, sending clear signals for body functions. People with a strong circadian rhythm tend to follow their regular times for sleeping and activity, even with schedule or season changes. With a weak circadian rhythm, light and schedule changes are more likely to disrupt the body clock. People with weaker rhythms are more likely to shift their sleep and activity times with the seasons or schedule changes.

A new study involved 2,183 people with an average age of 79 who did not have dementia at the start of the study. Researchers reviewed heart monitor data for various measures to determine circadian rhythm strength. These measures included relative amplitude, which is a measure of the difference between a person's most active and least active periods. High relative amplitude signified stronger circadian rhythms.

Researchers divided participants into three groups, comparing the high group to the low group. A total of 31 of 728 people in the high group developed dementia, compared to 106 of the 727 people in the low group. After adjusting for factors such as age, blood pressure, and heart disease, researchers found when compared to people in the high group, those in the low, weaker rhythm group had nearly 2.5 times the risk of dementia, with a 54% increased risk of dementia for every standard deviation decrease in relative amplitude.

Association Between Circadian Rest-Activity Rhythms and Incident Dementia in Older Adults

Aging is associated with changes in circadian rhythms. Rest-activity rhythms (RARs) measured using accelerometers are markers of circadian rhythms. Altered circadian rhythms may be risk factors of neurocognitive outcomes; however, results are mixed. This was a retrospective examination of data from the Atherosclerosis Risk in Communities (ARIC) study. ARIC participants who wore the a long-term continuous monitoring patch in 2016-17 for ≥3 days and were free of prevalent dementia were included. RARs were derived from investigational accelerometer data from the patch.

Of the 2,183 participants (age 79 ± 4.5 years), 176 (8%) developed dementia. The median follow-up time was 3 years, and the mean patch wear time was 12 days. After multivariable adjustment, each 1 standard deviation decrement in relative amplitude and 1-SD increment in intradaily variability were associated with 54% and 19% greater risk of dementia, respectively. Further research to determine whether circadian rhythm interventions can reduce dementia risk is warranted.

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/