LongeCityNews Last Updated: 05 March 2026 - 07:12 AM

The longevity industry will at some point diffuse into the broader pharmaceutical and biotech industries. It will cease to be so distinct in culture, technology, and regulation as to merit the drawing of firm lines. Treating aging as a medical condition is no longer looked upon as strange by the powers that be, even though the public at large has yet to catch up entirely to this new viewpoint. This relatively new environment of approval means that sizable funding is available, and indeed deployed in large amounts to advance the cause, both by private and public sources.

One of the US government programs in which program managers have become very sympathetic to the cause of treating aging is ARPA-H, portions of which one might think of as spiritual successors to the attitudes and aims of DARPA, except that the focus is progress in medical technology specifically. That clinical trials are so enormously expensive to prepare for and run is the fault of government regulatory bodies, a mess created over decades. Now another arm of government will feed public funds into that process to enable more groups to make progress in passing the financial hurdle that regulators created. As is usually the case, however, it is largely the already well funded, high-profile initiatives that receive that assistance; if one is connected enough to have a large chance of obtaining major government funding, one is connected enough to be able to raise just as much from private sources, and have probably already done so.

Regardless, medicine is a highly regulated industry, and this is how the game is played in any industry in which government appointees exert such a large degree of control over what does and does not happen. In these years in which the first therapies that might slow aging (or in a few cases selectively reverse aging) are making their way into clinical trials, most groups are indeed trying to play the game as it exists, with all of its flaws, as in the bigger picture it is vital to demonstrate to the world at large that the treatment of aging can be real. An increasing number of companies are looking for alternative paths, however, such as those setting up their initial clinical trials in much less costly locations, and intending to initially prove their worth and provide access via medical tourism. From a very high level perspective, the most important outcome for the next decade or two is that therapies for aging, as many different approaches as possible, are meaningfully tested in humans - however that outcome is achieved. Even a few successes will give rise to a massively larger industry, with enough weight behind it to meaningfully change the way in which medical development takes place.

ARPA-H pours millions into healthspan-focused human trials

The US Government, via its Advanced Research Projects Agency for Health (ARPA-H) initiative, is putting up to $144 million into multiple projects aimed at extending healthspan - the years people live in good health. Through its PROSPR program, ARPA-H is funding seven research teams working to treat aging as a tractable biological process, and proving, in humans, that intervening earlier can help people stay healthier for longer.

Short for "Proactive Solutions for Prolonging Resilience," PROSPR's goal is to overcome one of the key challenges that has limited clinical development in geroscience: aging is slow, and its associated diseases and conditions can take years or decades to emerge, making conventional trials unwieldy and expensive. The initiative aims to use longitudinal human data to identify early, actionable biomarkers that respond before late-stage outcomes appear. Those biomarkers are intended to serve as surrogate endpoints that can show, within one to three years, whether an intervention is plausibly shifting an individual's trajectory toward better function, resilience, and quality of life.

Longevity biotech Cambrian has been awarded up to $30.8 million to support human trials of a daily, oral, next-generation rapamycin analog intended to selectively inhibit mTORC1. The company views dysregulated mTORC1 signaling as a key driver of the metabolic decline that accumulates with age, and it is tying its program to "intrinsic capacity," a composite measure of physical and metabolic resilience that declines over time.

Linnaeus has been awarded up to $22 million to advance a drug targeting the G protein-coupled estrogen receptor (GPER) into human trials for healthspan preservation. Interestingly, the company is building on its work in oncology, where more than 100 cancer patients have been treated with its drug (LNS8801) in early human trials and signals observed in those patients suggested potential translation into aging-related benefits.

The longevity industry will at some point diffuse into the broader pharmaceutical and biotech industries. It will cease to be so distinct in culture, technology, and regulation as to merit the drawing of firm lines. Treating aging as a medical condition is no longer looked upon as strange by the powers that be, even though the public at large has yet to catch up entirely to this new viewpoint. This relatively new environment of approval means that sizable funding is available, and indeed deployed in large amounts to advance the cause, both by private and public sources.

One of the US government programs in which program managers have become very sympathetic to the cause of treating aging is ARPA-H, portions of which one might think of as spiritual successors to the attitudes and aims of DARPA, except that the focus is progress in medical technology specifically. That clinical trials are so enormously expensive to prepare for and run is the fault of government regulatory bodies, a mess created over decades. Now another arm of government will feed public funds into that process to enable more groups to make progress in passing the financial hurdle that regulators created. As is usually the case, however, it is largely the already well funded, high-profile initiatives that receive that assistance; if one is connected enough to have a large chance of obtaining major government funding, one is connected enough to be able to raise just as much from private sources, and have probably already done so.

Regardless, medicine is a highly regulated industry, and this is how the game is played in any industry in which government appointees exert such a large degree of control over what does and does not happen. In these years in which the first therapies that might slow aging (or in a few cases selectively reverse aging) are making their way into clinical trials, most groups are indeed trying to play the game as it exists, with all of its flaws, as in the bigger picture it is vital to demonstrate to the world at large that the treatment of aging can be real. An increasing number of companies are looking for alternative paths, however, such as those setting up their initial clinical trials in much less costly locations, and intending to initially prove their worth and provide access via medical tourism. From a very high level perspective, the most important outcome for the next decade or two is that therapies for aging, as many different approaches as possible, are meaningfully tested in humans - however that outcome is achieved. Even a few successes will give rise to a massively larger industry, with enough weight behind it to meaningfully change the way in which medical development takes place.

ARPA-H pours millions into healthspan-focused human trials

The US Government, via its Advanced Research Projects Agency for Health (ARPA-H) initiative, is putting up to $144 million into multiple projects aimed at extending healthspan - the years people live in good health. Through its PROSPR program, ARPA-H is funding seven research teams working to treat aging as a tractable biological process, and proving, in humans, that intervening earlier can help people stay healthier for longer.

Short for "Proactive Solutions for Prolonging Resilience," PROSPR's goal is to overcome one of the key challenges that has limited clinical development in geroscience: aging is slow, and its associated diseases and conditions can take years or decades to emerge, making conventional trials unwieldy and expensive. The initiative aims to use longitudinal human data to identify early, actionable biomarkers that respond before late-stage outcomes appear. Those biomarkers are intended to serve as surrogate endpoints that can show, within one to three years, whether an intervention is plausibly shifting an individual's trajectory toward better function, resilience, and quality of life.

Longevity biotech Cambrian has been awarded up to $30.8 million to support human trials of a daily, oral, next-generation rapamycin analog intended to selectively inhibit mTORC1. The company views dysregulated mTORC1 signaling as a key driver of the metabolic decline that accumulates with age, and it is tying its program to "intrinsic capacity," a composite measure of physical and metabolic resilience that declines over time.

Linnaeus has been awarded up to $22 million to advance a drug targeting the G protein-coupled estrogen receptor (GPER) into human trials for healthspan preservation. Interestingly, the company is building on its work in oncology, where more than 100 cancer patients have been treated with its drug (LNS8801) in early human trials and signals observed in those patients suggested potential translation into aging-related benefits.

Using brain clock models that analyzed MRI images of the brains of elderly people who underwent one year of resistance training, researchers concluded that both heavy and moderate resistance training slow brain aging [1].

The broad benefits

Exercise has been linked to many benefits, such as lowering blood pressure, slowing down cancer progression, preventing fitness decline in old age, and lowering biological age. We have also recently reported an association between exercise variety and a lower risk of mortality.

Exercise has also been linked to better brain health; studies suggest that it can improve cognition in older people, offer a protective effect against Alzheimer’s disease (however, only to a certain point), and, in some cases, help to alleviate age-related cognitive decline. The impact of exercise on brain structures was also investigated. Exercise has been shown to affect brain volume, specifically the hippocampus [2, 3]. However, there is a variability in how individuals respond to exercise [4]. Additionally, those previous studies have notable limitations, such as short-term interventions, and often investigate only a single brain region, which can miss global changes in the brain.

The authors of this study decided to address some of those shortcomings. Their study included 309 adults, between 62 and 70 years old, who were randomized into three groups: heavy resistance training (HRT), moderate-intensity resistance training (MIT), and a non-exercise control group. The exercise groups followed a 1-year program combining resistance and functional training to improve strength, endurance, and balance. Then, the researchers assessed how the training impacted the brain health.

Global changes with local enhancers

Previous studies suggested that specific brain regions are involved in exercise-mediated cognitive improvement [2]; however, they didn’t determine whether only certain regions are affected or whether exercise affects the brain beyond the identified regions.

In this study, brain connectivity analysis indicated that a year of heavy resistance training, but not moderate-intensity resistance training, resulted in significantly greater activity than in the group that didn’t exercise. Significant clusters of activity were especially evident in prefrontal regions, as well as in motor cortex and superior parietal areas of the brain. Those regions are responsible for such functions as attention, executive control, and working memory [5, 6]. The observed strengthening of connections in those specific brain regions might suggest a mechanism that links exercise and cognitive improvements that should be investigated further.

However, while these effects were more prominent in some brain regions, this study suggests that exercise-related changes were present beyond those specific regions, indicating general improvements in brain health. The researchers also suggest that these broad effects are likely due to exercise-induced “systemic molecular and vascular processes”; however, this remains to be experimentally tested.

Exercising your way to slower brain aging

In the next step, the researchers used recently developed brain clocks, a new class of biomarkers of brain health. Those models combine different imaging modalities, in this case functional magnetic resonance imaging (rs-fMRI), to estimate brain age. The difference between the model’s estimated age and the participant’s chronological age reflects the speed of brain aging. The researchers trained brain clock models on an independent dataset of 2,433 participants in a different study and used those models in the 309 participants of this study.

The brain age gap (BAG), which indicates “whether the brain appears older or younger than the chronological age at a given time point,” decreased in the exercise groups following one year of exercise and one year after the exercise regimen stopped. For the heavy resistance training group, the researchers observed a 1.4-year reduction at one year after the exercise regimen began and a 1.84-year reduction one year after the exercise regimen ended. For the moderate-intensity resistance training group, reductions of 1.39 and 2.26 years were observed at those time points, respectively. As expected, the group that didn’t exercise showed no significant changes in BAGs.

Those results suggest the brains of people who exercised were younger than their chronological age and that the beneficial effects of training are lasting, as the positive impact is seen even a year after the training regimen ended.

Those changes are consistent with the effect sizes reported in other studies examining the impact of lifestyle factors, such as physical activity or education, on the aging brain [7, 8]. Even though such changes appear rather modest, their overall effect is meaningful. As the authors explain: “Given that brain aging is a gradual and cumulative process, differences of this magnitude are considered biologically meaningful and have been linked to improved brain integrity and cognitive performance in older adults.”

Changes in BAGs were also correlated with changes in leg strength but were significant only in the moderate exercise group. The authors offer explanations for why only the moderate-intensity resistance training group shows the association. One of them might be the non-linear dose-response relationship, meaning that higher levels of exercise do not necessarily produce greater effects. There may also be varying baseline fitness levels among study participants, varying individual responsiveness to training, or measurement noise.

Good design with limitations

In summary, the obtained results suggest that both heavy and moderate resistance training slow brain aging, indicating that resistance training, among other modifiable lifestyle factors, can improve brain health in the elderly. What’s more, developing these models allows other researchers to use them to test the impact of other interventions on brain health.

This study, while relatively small, uses a randomized, controlled design, making it a stronger methodological approach than previous cross-sectional studies. However, the results may not be broadly generalizable to everyone, as the study sample consisted of high-income Europeans rather than a representative sample of the population.

Literature

[1] Gonzalez-Gomez, R., Demnitz, N., Coronel, C., Gates, A. T., Kjaer, M., Siebner, H. R., Boraxbekk, C. J., & Ibanez, A. M. (2026). Randomized controlled trial of resistance exercise and brain aging clocks. GeroScience, 10.1007/s11357-026-02141-x. Advance online publication.

[2] Erickson, K. I., Voss, M. W., Prakash, R. S., Basak, C., Szabo, A., Chaddock, L., Kim, J. S., Heo, S., Alves, H., White, S. M., Wojcicki, T. R., Mailey, E., Vieira, V. J., Martin, S. A., Pence, B. D., Woods, J. A., McAuley, E., & Kramer, A. F. (2011). Exercise training increases size of hippocampus and improves memory. Proceedings of the National Academy of Sciences of the United States of America, 108(7), 3017–3022.

[3] Jonasson, L. S., Nyberg, L., Kramer, A. F., Lundquist, A., Riklund, K., & Boraxbekk, C. J. (2017). Aerobic Exercise Intervention, Cognitive Performance, and Brain Structure: Results from the Physical Influences on Brain in Aging (PHIBRA) Study. Frontiers in aging neuroscience, 8, 336.

[4] von Cederwald, B. F., Johansson, J., Riklund, K., Karalija, N., & Boraxbekk, C. J. (2023). White matter lesion load determines exercise-induced dopaminergic plasticity and working memory gains in aging. Translational psychiatry, 13(1), 28.

[5] Friedman, N. P., & Robbins, T. W. (2022). The role of prefrontal cortex in cognitive control and executive function. Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology, 47(1), 72–89.

[6] Menon, V., & D’Esposito, M. (2022). The role of PFC networks in cognitive control and executive function. Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology, 47(1), 90–103.

[7] Dunås, T., Wåhlin, A., Nyberg, L., & Boraxbekk, C. J. (2021). Multimodal Image Analysis of Apparent Brain Age Identifies Physical Fitness as Predictor of Brain Maintenance. Cerebral cortex (New York, N.Y. : 1991), 31(7), 3393–3407.

[8] Steffener, J., Habeck, C., O’Shea, D., Razlighi, Q., Bherer, L., & Stern, Y. (2016). Differences between chronological and brain age are related to education and self-reported physical activity. Neurobiology of aging, 40, 138–144.

TDP-43 is a protein only relatively recently discovered to undergo pathological modification and aggregation in the aging brain. Much like amyloid-β, α-synuclein, and tau, this aggregation is thought important in the progression of specific neurodegenerative conditions. Here, researchers present evidence for TDP-43 aggregation to contribute to lost function in vascular dementia. Vascular dementia arises from a reduced blood supply to the brain, or other issues in the vasculature supplying brain tissue with the oxygen and nutrients it needs. The brain operates at the edge of metabolic capacity at the best of times, and as that supply diminishes with age, function suffers. Can some of the consequent damage done to the brain be prevented? Obviously it would be ideal to maintain a healthy vasculature instead of trying to compensate for vascular aging, but the research community does spend a lot of time looking at possible compensatory approaches, ways to sabotage at least some of the maladaptive reactions to the damage and dysfunction of aging.

Vascular dementia (VaD) ranks as the second most common cause of dementia worldwide and is linked to the highest mortality rate among dementia subtypes. A key driver of VaD pathogenesis is chronic cerebral hypoperfusion (CCH), a state of persistently reduced blood flow to the brain stemming from cerebrovascular compromise. A hallmark of VaD, CCH can diminish cerebral blood flow by as much as 40%, triggering hypoxia-induced cellular stress. This includes oxidative damage, mitochondrial failure, and heightened neuroinflammation, which collectively impair blood-brain barrier integrity and promote white matter lesion (WML) formation.

Recent evidence points to Tar DNA-binding protein 43 (TDP-43) as a potential mediator in this cascade. While TDP-43′s pathological role is well-established in amyotrophic lateral sclerosis (ALS), frontotemporal dementia, and Alzheimer's disease (AD), its involvement in VaD is poorly understood. In healthy neurons, TDP-43 is crucial for synaptic function and stress response. Under pathological conditions, however, it undergoes detrimental modifications, including hyperphosphorylation, nuclear-to-cytoplasmic mislocalization, and aggregation that are common processes across neurodegenerative diseases. These aberrant forms of TDP-43 lose their normal function and can acquire toxic properties, potentially exacerbating neuroinflammation. While TDP-43 pathology is a well-established feature of several neurodegenerative diseases, its potential role in the context of cerebrovascular injury remains largely unexplored.

This study demonstrates that CCH, a key feature of VaD, triggers pathological TDP-43 changes, namely cytoplasmic mislocalisation and hyperphosphorylation, in both in vivo and in vitro models. In a mouse model of VaD, time-dependent cytoplasmic accumulation of TDP-43 and pTDP-43 was observed in cortical and hippocampal neurons, with elevated pTDP-43 despite stable total TDP-43 levels, implicating phosphorylation in its aberrant redistribution. These results mirror hallmark features of TDP-43 proteinopathies in neurodegenerative diseases, such as ALS and AD, and suggest that similar mechanisms may be triggered by vascular insults.

Link: https://doi.org/10.1002/alz.71196