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22 January 2026 - 11:24 PM
Towards Small Molecule Reprogramming as a Basis for Rejuvenation Therapies 22 January 2026 - 07:22 PM
Exposing cells to the Yamanaka transcription factors for a short period of time can produce rejuvenation of nuclear DNA structure, epigenetic regulation of that structure, and cell function. Cells in aged tissues become functionally younger following this partial reprogramming, expressing genes in the same way that younger cells do. Initial efforts to build treatments based on this finding have focused on gene therapy approaches, but gene therapy technologies come attached to thorny delivery issues. It remains somewhere between very difficult and impossible to deliver gene therapies to many of the tissues in the body, or to deliver systemically and evenly throughout the body.
Small molecule drugs, on the other hand, can be much better at achieving body-wide distribution of effects. If looking to the near future of the reprogramming field and its efforts to produce rejuvenation therapies, it seems likely that small molecule approaches to reprogramming will give rise to rejuvenation therapies that can affect the whole body well in advance of the development of any effective solutions for the long-standing delivery challenges associated with gene therapies. That said, the present small molecule combinations tested in animal studies still need a fair amount of work in order to produce an outcome acceptable to regulators. The discovery and optimization of entirely new classes of small molecule may be needed.
Molecular time machines unleashed: small-molecule-driven reprogramming to reverse the senescence
The core mechanism by which small-molecule compounds induce cellular reprogramming lies in their ability to mimic transcription factor functions, regulate intracellular signaling networks, and reverse aging-associated epigenetic alterations. Research indicates that specific combinations of small molecules can effectively activate pluripotency gene networks while simultaneously suppressing aging-related pathways, thereby achieving a reversal of cellular states.
First, small-molecule-compound-induced cellular reprogramming typically rewards the involvement of epigenetic modulators. Although the addition is not mandatory in all protocols - its necessity depends on factors such as reprogramming strategy, target cell type, and desired efficiency - epigenetic regulation plays a crucial role in cellular reprogramming. Research indicates that the reprogramming of fibroblasts often requires reversing differentiation-associated epigenetic barriers. Small-molecule epigenetic modulators actively clear these barriers: DNA methylation inhibitors (e.g., 5-aza-cytidine) reduce methylation levels at pluripotency gene promoters to enhance Oct4/Sox2 expression, while histone deacetylase (HDAC) inhibitors (e.g., Valproic acid, VPA) increase histone acetylation, open chromatin structures, and accelerate reprogramming.
Notably, epigenetic alterations have been identified as one of the core hallmarks of aging. During the aging process, the epigenome of cells and tissues undergoes significant and systematic changes. These alterations are not merely consequences of aging but also driving forces behind it. However, epigenetic modulators can reshape the epigenetic landscape of aging cells and reverse aging. Research has found that tranylcypromine (blocking H3K4me2 demethylation) and RepSox significantly reduces SA-β-gal activity in aged fibroblasts, upregulates pluripotency genes such as OCT4 and Nanog, and simultaneously downregulates age-associated stress response genes p21, p53, and IL6. This epigenetic reprogramming not only restores cellular proliferative capacity but also improves oxidative stress and heterochromatin loss, reversing aging characteristics across multiple dimensions.
Second, cellular signaling pathways serve as pivotal regulatory hubs in chemical reprogramming, precisely intervening in cellular fate by integrating epigenetic remodeling, metabolic reprogramming, and microenvironmental signals. Unlike the "hard switching" of genetic reprogramming (such as transcription factors), small molecules regulate signaling pathways more like a finely adjustable "dial," enabling more precise and controllable spatiotemporal dynamic regulation. None of these signaling pathways operate independently. The success of chemical reprogramming in combating aging relies on constructing an ecosystem of interacting signaling pathways that simulates embryonic development.
View the full article at FightAging
How Senescent Astrocytes Don’t Support Neurons 22 January 2026 - 05:04 PM
Resesarchers have found that thrombospondin-1 (TSP-1), a compound that is critical in growing brain synapses, is secreted by normal astrocytes but not senescent ones.
Senescence is harmful to the brain
It is well-known that cellular senescence causes brain damage and impairment. The SAMP8 mouse, which is used in this study, has accelerated senescence and quickly develops related brain problems [1]. For example, last year, we reported that senescent microglia are overly aggressive in pruning brain synapses.
This research, however, focuses on astrocytes, other resident brain cells that fulfill a wide variety of maintenance functions [2]. The authors of this paper note that the exact effects of astrocytic senescence on neural synapses have not been particularly well-studied. To remedy this, they closely examined SAMP8 mice to determine how their senescent astrocytes might be indirectly affecting their neurons.
Direct cellular contact is not required
In their first experiments, the researchers verified that hippocampal astrocytes derived the SAMP8 mice were indeed more senescent than those of a control group, including increased expression of the characteristic SA-β-gal. Then, they developed conditioned media (CM) from these astrocytes and discovered that unmodified neural stem cells derived from wild-type mouse embryos were much more able to grow synapses in the CM derived from control astrocytes than in CM from SAMP8 astrocytes. These results held whether the CM was derived from astrocytes differentiated from neural stem cells (NSCs) or from astrocytes directly derived from SAMP8 animals.
The researchers then investigated the molecules present in this CM. As previous work had found that TSP-1 decreases with aging [3] and that its function is critical in cognitive maintenance [4], they took a close look at this particular factor, finding decreases in both the TSP-1 protein and the expression of the Thbs1 gene that encodes it in mice. Once again, these results were verified in both NSC-derived astrocytes and directly taken astrocytes, and unsurprisingly, TSP-1 was also decreased in the hippocampi of SAMP8 mice compared to controls.
Focusing on TSP-1
The biological effects were confirmed through the use of gabapentin, a compound that blocks the receptor of TSP-1. Introducing gabapentin nullified the differences between SAMP8-derived CM and control-derived CM.
Encouraged, the researchers then did the opposite in two ways: they simply added TSP-1 into CM, and they engineered SAMP8 astrocytes to overexpress Thbs1 and then derived CM from those. Both of these approaches had the desired effect: neurons exposed to either one of these CMs were much more able to develop synapses.
It is clear that further work needs to be done to determine whether or not TSP-1 can be used as a functioning strategy in living organisms. The researchers did not attempt to use TSP-1 to treat mice, particularly naturally aged mice, nor did they create a SAMP8 or other model mouse that overexpresses Thbs1. Combined with cognitive tests, such experiments could inform the research world whether or not this might be a viable path to restoring neuroplasticity and cognitive function to older people.
Literature
[1] Akiguchi, I., Pallàs, M., Budka, H., Akiyama, H., Ueno, M., Han, J., … & Hosokawa, M. (2017). SAMP8 mice as a neuropathological model of accelerated brain aging and dementia: Toshio Takeda’s legacy and future directions. Neuropathology, 37(4), 293-305.
[2] Phatnani, H., & Maniatis, T. (2015). Astrocytes in neurodegenerative disease. Cold Spring Harbor perspectives in biology, 7(6), a020628.
[3] Clarke, L. E., Liddelow, S. A., Chakraborty, C., Münch, A. E., Heiman, M., & Barres, B. A. (2018). Normal aging induces A1-like astrocyte reactivity. Proceedings of the National Academy of Sciences, 115(8), E1896-E1905.
[4] Cheng, C., Lau, S. K., & Doering, L. C. (2016). Astrocyte-secreted thrombospondin-1 modulates synapse and spine defects in the fragile X mouse model. Molecular brain, 9(1), 74.
View the article at lifespan.io
The Longevity World Forum Confirms Madrid for 2026 22 January 2026 - 02:44 PM
The Longevity World Forum announces its move to Madrid, reinforcing its international positioning with a new location aligned with its growth and leadership objectives in the field of longevity science and healthy ageing.
The Spanish capital beats the cities that were postulated as possible venues for the next edition and thus adds an important asset to its program of benchmark events related to science, research and technological innovations.
A new stage is beginning that will culminate with the celebration of the 4th edition of the Longevity World Forum from 18 to 20 February 2026. An edition that, in the words of Francisco Larrey, director of this project, “raises the profile of an event that aims to revolutionize knowledge and practices in the field of longevity. In this sense, bringing Longevity World Forum to Madrid will enrich the link between the region and science by bringing together international experts, scientists and technologists to learn about the latest research in this field”.
2024: A successful edition
In October 2024, Alicante hosted the third edition of the Longevity World Forum. A global event which, over two days, brought together nearly 1,000 people around a program with top international experts. A program that addressed issues on preventive medicine, epigenetics and lifestyle and their impact on longevity and healthy ageing.
The Longevity World Forum announces its move to Madrid, reinforcing its international positioning with a new location aligned with its growth and leadership objectives in the field of longevity science and healthy ageing.
The event confirmed its global relevance by presenting itself as an international meeting place for the exchange of ideas and the creation of synergies between different actors in the sector.
2026: An opportunity for international projection
From 18 to 20 February 2026, Longevity World Forum will hold its fourth edition at the La Nave innovation center, the first in the key international city of Madrid.
Within this framework, the congress will reinforce its role as the epicenter of the scientific community, the innovative ecosystem and the industry linked to the sector. To this end, it is already working on a hybrid format that will allow both in-person and virtual attendance.
It is also announcing new features, such as the inclusion of a conference aimed at start-ups to generate a new pole of attraction for emerging companies related to the longevity industry.
The conference is aimed at anyone with scientific, business, social and economic interests related to longevity. This includes healthcare professionals and researchers, companies in the sector, E-Health startups, students and anyone curious about this topic. The global accessibility of the event will allow the participation of interested people from all over the world, breaking geographical barriers and promoting a global community of knowledge and collaboration.
More information: www.longevityworldforum.com
View the article at lifespan.io
Is Ferroptosis Important in Muscle Aging? 22 January 2026 - 11:22 AM
The aging of muscle tissue leading to loss of muscle mass (sarcopenia) and muscle strength (dynapenia) is a microcosm of aging in general, in that many different groups promote many different views of the relative importance of many different mechanisms. All of these mechanisms do in fact exist - muscle aging is a complex interplay of many interacting issues - but it is likely that any given view on the importance of any given specific mechanism will turn out to be wrong. The only practical way to establish the importance of a mechanism of muscle aging is to develop a means of blocking or repairing just that mechanism in isolation of all of the others, and observe the result. This applies as much to the examination of ferroptosis noted here as it does to any of the other mechanisms involved in muscle aging.
Age-related decline in physical function is a hallmark of aging and a major driver of morbidity, disability, and loss of independence in older adults, yet the molecular processes linking muscle aging to functional deterioration remain incompletely defined. Emerging evidence implicates ferroptosis, defined as iron-dependent, lipid peroxidation-driven cell death, as a compelling but underexplored contributor to age-related muscle wasting and weakness. Although ferroptosis signatures appear in aged muscle across cellular, animal, and human studies, their causal role in functional decline has not been clearly established.
Here, we synthesize current evidence to propose a framework in which iron dyshomeostasis, impaired antioxidant defenses, and dysregulated ferritinophagy converge to create a pro-ferroptotic milieu that compromises muscle energetics, structural integrity, and regenerative capacity. We delineate key knowledge gaps, including the absence of ferroptosis-specific biomarkers in human muscle and limited longitudinal data linking ferroptotic stress to mobility outcomes. Finally, we highlight potential therapeutic opportunities targeting iron handling and lipid peroxidation pathways. A better understanding of the contribution of ferroptosis to muscle aging may enable development of mechanistically informed biomarkers and interventions to preserve strength and mobility in older adults.
Link: https://doi.org/10.1111/acel.70367
View the full article at FightAging
