LongeCityNews Last Updated: 12 December 2025 - 11:31 AM

In Aging Cell, researchers have described how an age-related deficiency in another compound leads the antioxidant FoxO1 to contribute to bone deterioration in osteoporosis by siphoning from a bone-building pathway.

A harmful antioxidant?

Because they fight against harmful reactive oxygen species (ROS), antioxidants, both external and internal, are normally viewed as having positive effects against aging. This includes bone tissue, as previous work has found that knocking out FoxO1 harms bone formation while inducing its overexpression leads to more bone building [1].

On the other hand, another team of researchers has found that knocking out FoxO1 in osteoblasts, the cells responsible for building bone, can lead to greater bone formation rather than any depletion [2]. Those researchers discovered some of the reasons why, finding that FoxO1 can have a negative effect on the Wnt/β-catenin signaling pathway in older animals [3].

This paper builds upon that research, focusing on MACF1, a protein that diminishes with age and has been pinpointed as playing a key role in osteoporosis. Unsurprisingly, it too plays a crucial role in the Wnt/β-catenin signaling pathway that osteoblasts need to function [4]. These researchers, therefore, decided to investigate the relationship between FoxO1 and MACF1 in this context.

MACF1 knockout leads to oxidative stress

The researchers took populations of mesenchymal stem cells (MSCs), some of which had MACF1 knocked out, and exposed them to hydrogen peroxide, a strong oxidant. Runx2 and Alp, two factors necessary for the differentiation and function of osteoblasts, were significantly reduced by both MACF1 knockout and by oxidative stress. While either MACF1 knockout or oxidative stress had measurable negative effects on mineralization, mineralization loss was especially profound in the MACF1-knockout cells exposed to the peroxide. Overall, this experiment led the researchers to hold that “the absence of MACF1 in cells results in persistent and high levels of ROS, leading to chronic oxidative stress and inhibiting the differentiation of osteoblastic cells.”

A further experiment on mice found that oxidative stress was indeed a key link in this relationship. Untreated, mice with MACF1 knocked out experience significantly greater frailty and live significantly shorter lives than unmodified mice, having a 50% mortality rate at only 19 months of age. Treatment with the antioxidant NAC increased this survival rate to 100%, the same as wild-type mice, and restored some of the frailty markers.

Too focused on survival to differentiate

The researchers then turned to the main thrust of their paper, linking MACF1, β-catenin, and FoxO1. They found that exposing cells to hydrogen peroxide significantly reduced β-catenin, but supplying them with NAC did not affect it. MACF1-knockout cells always had elevated levels of FoxO1, whether or not they were exposed to hydrogen peroxide. A fluorescence measurement found that treatment with NAC reduced the intensity of FoxO1.

Most crucially, the researchers found that FoxO1 “seizes” β-catenin away from TCF7, a crucial compound in osteoblast differentiation. This altered the cells’ fate; instead of properly differentiating into osteoblasts, the affected cells were focused on fighting their own oxidation. The MACF1 knockdown spurred this transition, causing FoxO1 and β-catenin to co-locate in greater amounts than in unmodified cells. Treatment with NAC partially alleviated this condition.

This research pinpoints MACF1 as a key target in future work, particularly since it dovetails with other research showing that MACF1 plays a key function in the stability of other cells, including neurons [5]. While treatment with antioxidants, which reduces the need for FoxO1, appears to be beneficial in allowing osteoblasts to properly differentiate, restoring the levels of MACF1, a key compound that decreases with age, appears to be necessary. Further work will have to be done to determine how this may be accomplished.

Literature

[1] Rached, M. T., Kode, A., Xu, L., Yoshikawa, Y., Paik, J. H., DePinho, R. A., & Kousteni, S. (2010). FoxO1 is a positive regulator of bone formation by favoring protein synthesis and resistance to oxidative stress in osteoblasts. Cell metabolism, 11(2), 147-160.

[2] Xiong, Y., Zhang, Y., Guo, Y., Yuan, Y., Guo, Q., Gong, P., & Wu, Y. (2017). 1α, 25-Dihydroxyvitamin D3 increases implant osseointegration in diabetic mice partly through FoxO1 inactivation in osteoblasts. Biochemical and biophysical research communications, 494(3-4), 626-633.

[3] Xiong, Y., Zhang, Y., Zhou, F., Liu, Y., Yi, Z., Gong, P., & Wu, Y. (2022). FOXO1 differentially regulates bone formation in young and aged mice. Cellular Signalling, 99, 110438.

[4] Yin, C., Tian, Y., Hu, L., Yu, Y., Wu, Z., Zhang, Y., … & Qian, A. (2021). MACF1 alleviates aging‐related osteoporosis via HES1. Journal of cellular and molecular medicine, 25(13), 6242-6257.

[5] Okenve-Ramos, P., Gosling, R., Chojnowska-Monga, M., Gupta, K., Shields, S., Alhadyian, H., … & Sanchez-Soriano, N. (2024). Neuronal ageing is promoted by the decay of the microtubule cytoskeleton. PLoS biology, 22(3), e3002504.

The glymphatic system parallels blood vessels where they enter the brain, providing a path for drainage of cerebrospinal fluid from the brain into the body. The other well described path is through channels in the cribriform plate bone. These drainage routes become dysfunctional with age, allowing metabolic waste to build up in the brain, and thus contributing to the dysfunctional environment that causes pathology and neurodegeneration.

An approach to measure drainage of cerebrospinal fluid through the glymphatic system via magnetic resonance imaging was developed relatively recently, known by the unwieldy name of diffusion tensor imaging analysis along the perivascular space (DTI-ALPS). DTI-ALPs has been having its time in the sun over the past few years, with numerous research groups working to expand the body of data for this measurement in various patient populations. Today's open access paper is an example of this sort of work, focused on patients with cerebral small vessel disease.

Cerebral small vessel disease, also known as microangiopathy, emerges from a combination of endothelial dysfunction in microvessels, a loss of microvessel density that impairs blood flow, and other issues that affect the integrity and function of the smallest vessels that support brain tissue. It is worth considering that the aspects of aging that harm the vasculature likely also harm the near neighbor glymphatic system. That patients with cerebral small vessel disease also exhibit impaired glymphatic drainage of cerebrospinal fluid doesn't necessarily mean that one condition causes the other. They may both be emergent properties of the cell and tissue damage of aging, and likely each makes the other worse in a variety of different ways.

Glymphatic system impairment in cerebral small vessel disease: associations with perivascular space volume and cognition

Cerebral small vessel disease (CSVD) is a progressive cerebrovascular disease characterized by diverse clinical manifestations, especially neurocognitive dysfunction, a primary contributor to vascular cognitive impairment. The glymphatic system, a brain waste clearance system first described in 2012, facilitates the exchange of cerebrospinal fluid (CSF) with interstitial fluid (ISF). In this process, CSF enters the brain parenchyma via para-arterial perivascular spaces, passes through astrocytic aquaporin-4 (AQP4) water channels, and mixes with ISF before being cleared along perivenous routes, thereby promoting the removal of metabolic waste.

Recent evidence suggests that impaired glymphatic function may represent a final common pathway in the pathogenesis of dementia and has been increasingly implicated in the pathophysiology of CSVD. However, the relationship between glymphatic dysfunction and CSVD is likely bidirectional and multifactorial. On one hand, CSVD-related pathologies, such as endothelial dysfunction, blood-brain barrier disruption, and reduced arterial pulsatility, may impair glymphatic flow by compromising perivascular pumping mechanisms and fluid transport. On the other hand, impaired glymphatic clearance may exacerbate CSVD by allowing the accumulation of neurotoxic waste products, such as amyloid-β and tau proteins, and pro-inflammatory molecules within perivascular spaces, further damaging vascular integrity and promoting white matter injury.

We enrolled 120 CSVD patients [52 with no cognitive impairment (CSVD-NCI) and 68 with mild cognitive impairment (CSVD-MCI)] and 40 healthy controls. Glymphatic function was assessed using the left ALPS index derived from diffusion tensor imaging analysis along the perivascular space (DTI-ALPS). Group comparisons in the ALPS index and perivascular space (PVS) volume fraction (VF), and correlations among glymphatic function, perivascular burden, and cognition were analyzed.

Compared to healthy controls, CSVD patients showed decreased ALPS index and increased PVS VF in basal ganglia, caudate, putamen, and hippocampus, with more pronounced alterations in the left hemisphere. The ALPS index was inversely correlated with PVS VF in the basal ganglia (r = -0.232), thalamus (r = -0.213), caudate (r = -0.221), and putamen (r = -0.210) in CSVD. Furthermore, a lower ALPS index was associated with poorer performance in global cognition (r = 0.312), executive function (r = 0.242), processing speed (r = 0.264), and visuospatial function (r = 0.272). Finally, the ALPS index partially mediated the association between putamen-PVS VF and global cognitive function, especially in the left hemisphere. Our findings demonstrate that impaired glymphatic function was associated with enlarged basal ganglia PVS, especially in the putamen, and worse cognitive performance, highlighting its potential role in disease progression and cognitive decline in CSVD.

Happy holidays! Winter is in full swing for those of us in the Northern Hemisphere. It is a time for cozy nights by the fire and a great time to catch up on what has been happening at Lifespan News and LRI.

A cultural intelligence platform for effective advocacy

We are delighted to announce that the campaign to develop a cultural intelligence platform has been a success!

Thanks to donations from the community and Longevity Alliance members, the project will now start. The goal of the campaign was $100,000, and we managed to raise $104,395, taking us to 104% needed to start this important initiative.

About the project

Public trust is the key that opens all other doors. For a long time, the field of longevity research has needed better tools to gauge public opinion and cultivate that trust.

To achieve this, LRI is supporting the development of a cultural intelligence platform by the Public Longevity Group (PLG). The goal is to create tools for measuring public opinion. It will help us to evaluate media coverage and analyze social media engagement in the field. It will also help us to develop effective ways to communicate with audiences that have been overlooked.

The cultural intelligence platform is an AI-driven platform. It will be able to examine all kinds of information, such as media articles and journal papers. With this information, it will be able to track public sentiment in real time and can conduct A/B testing for advocacy messaging.

This set of tools will allow us to engage with audiences worldwide and in much more effective ways, such as by finding the best messaging for different demographic groups. This is excellent news, and our field urgently needs tools like this to support effective advocacy.

We will be reporting on progress and findings from the cultural intelligence platform in the coming years. Many thanks to everyone who helped to make this a reality.

Top longevity news stories of Autumn 2025

As usual, we have been busy bringing you the best in longevity journalism in these past weeks; here are some of the highlights.

Longevity medicine for everyone

Dr. Andrea Maier is a well known and respected researcher in the aging research field. She works at the National University of Singapore and runs her own company, Chi Longevity, which focuses on longevity medicine.

Many longevity centers provide what are effectively high-level healthcare services to rich clients. Andrea wants to go beyond that and has been working on ways to bring longevity medicine to the wider public.

With the NUS launching a clinical trial center focused on longevity, Arkadi Mazin caught up with Andrea. In this interview, he talked to her about the goal of longevity for everyone.

Multilingualism Is Associated With Delayed Aging

Anna Drangowska-Way brought us an interesting article about people who speak multiple languages and longevity. A recent paper suggested that there is a link between spoken languages and delayed aging.

While the exact reasons for this association are not clear, this does touch upon what we know about brain aging: staying mentally active and engaged gives one the motivation to keep going. The quote “The mind is just like a muscle – the more you exercise it, the stronger it gets and the more it can expand.” is apt here.

Anna speaks a number of languages herself, so that’s also good news for her! It isn’t too late to start learning a new language. With many language apps available today, it has never been easier to get started. You never know; it might just help you live a longer, healthier life.

Improving the Cultural Image of Longevity

The Alliance for Longevity Science, Arts & Entertainment (ALSAE) has recently launched. This new nonprofit organization aims to challenge misconceptions about longevity research.

Its goal is to engage with people who create culture in our societies. The organization already has a list of “cultural ambassadors” that includes Oscar- and Grammy-winning artists. Arkadi Mazin spoke with the founders about their goal to improve the cultural image of longevity.

Repairing our DNA

DNA damage is a primary reason we age. Over time, our DNA experiences imperfect repair or mutations. The burden of this damage grows over time and raises the risk of cancer and other age-related diseases.

Matter Bioworks is a new biotech company with a bold vision: to repair our DNA.

We spoke with Sam Sharifi, the Chief Scientific Officer at Matter Bio, who shared how this company plans to fix damaged DNA. Matter Bio plans to achieve this by replacing only the damaged parts of DNA using a transposon-based editor. This technique offers more fidelity than CRISPR gene editing, according to Sam.

The company is also exploring the potential of giving people multiple copies of beneficial genes, which might make it possible to make the genome more efficient and robust.

Indefinite lifespans are being discussed more often

We are likely some time from when aging becomes optional, but it is interesting to see the topic being discussed more often.

A recent poll by YouGov explored public sentiment about living indefinitely thanks to science. The fact that these discussions are happening at all shows there is a change from just ten years ago.

Unfortunately, the questions and even the available answers were a mixed bag, so what this survey ended up with was a somewhat confusing and contradictory set of responses. It does really prompt the question “Do the people making these polls consult with experts in the field before they publish them?”

Judge for yourself about what the public had thought of the question “if death were optional, would you still choose it?”

Building a scientific superintelligence

Professor George Church is a well-known name in the aging research field. He has an almost legendary reputation for entrepreneurship due to the number of companies he has co-founded.

Normally, he only plays advisory roles in these companies, so our interest was piqued when it was announced that he would be the Chief Scientist at the new Lila Sciences.

Lila has the goal of reinventing the scientific method. This company wants to use AI to advance science, but on a scale never seen before. Lila’s executives believe that they can create an AI capable of designing and running thousands of experiments at a time. This high throughput, along with AI’s ability to make unique connections, is an interesting idea.

Arkadi Mazin spoke with Professor Church to learn more about how that this company intends to create a scientific superintelligence.

Support the science for longer, healthier lives for all

While the world celebrates another trip around the sun, help us to turn ‘growing old’ into ‘staying young longer.’ Make a US tax-deductible gift so that we can continue to develop therapies to delay, prevent, and reverse age-related diseases.

We really are making a difference here at our research center in Mountain View, California. The Sharma Lab is conducting important research on senescent cells and therapeutic approaches to removing them. The Boominathan Lab is developing mitochondrial repair therapies, with a focus on the repair or replacement of damaged mitochondrial DNA and the maintenance of mitochondrial health.

Your help also supports our advocacy efforts and allows us to keep bringing you the latest rejuvenation biotech news. As a non-profit, we are free from commercial and government influence and are your trusted source for longevity-related news and information.

Help us accelerate the science and systems driving longer, healthier lives for all. Donate today!

Join the Lifespan Alliance

If you are interested in supporting us as a company, including the benefits of doing so, please consider becoming a member of the Lifespan Alliance.

We sincerely appreciate all the organizations that have partnered with us already. Your contributions are invaluable and enable us to persist in our vital research, advocacy, journalism, and educational efforts. Thank you for your support.

Finally, we would like to wish you all a happy holiday season and a fantastic new year!

Much of the benefit of stem cell therapies results from the signals released by those cells in the short time they survive in the body following transplantation. Much of that signaling is carried by extracellular vesicles, membrane-wrapped packages of molecules. Extracellular vesicle therapies can in principle become considerably less costly than stem cell therapies, because manufacture can be centralized, and because extracellular vesicles are much more readily stored and transported, but we are not there yet. Thus while extracellular vesicle therapy is certainly available to those with the time and patience to navigate the medical tourism space, or find suppliers and a cooperative physician inside the US, the schedule of 36 doses over 18 months used in this study is beyond the financial reach of most individuals at the present time. Still, it is quite interesting to see that the researchers demonstrated improvement in cognitive function in the aged monkeys assessed in the study.

Aging humans and non-human primates both exhibit a similar pattern of cognitive decline beginning in middle age that is characterized by progressive impairments in rule learning, executive function, and working and recognition memory-functions often associated with dysfunction of prefrontal and medial temporal lobe regions. The heterogeneity and inter-subject variability in aging and age-related cognitive impairments present challenges for developing effective therapeutics and can be attributed to differing degrees of cortical white matter (WM) damage and alterations to local and long-range prefrontal and temporal networks.

A promising therapeutic that has been shown to be efficacious in mitigating WM damage and improving cognitive function in rodent models is mesenchymal cell-derived extracellular vesicles (MSC-EVs). In the present study, late middle-aged rhesus monkeys were systemically administered monkey-derived MSC-EVs every 2 weeks for 18 months. We demonstrate that MSC-EV treatment improves spatial working memory and decreases the frequency of perseverative responses with largely no effects on recognition memory. These cognitive improvements were associated with increases in MRI diffusion measures of WM structural integrity over time as well as preservation of inter-network functional connectivity as measured by resting-state functional MRI.

These findings suggest that MSC-EV treatment can slow or reverse age-related cognitive decline while strengthening WM integrity and improving functional connectivity in late middle-aged rhesus monkeys.

Link: https://doi.org/10.1007/s11357-025-01992-0