LongeCityNews Last Updated: 23 December 2025 - 02:05 AM

Lipofuscin is the name given to a mix of modified proteins, lipids, and other compounds that accumulate with age in long-lived cells. The accumulation of lipofuscin has long been considered a form of damage by a minority of researchers; removal of lipofuscin was an early call to action for the Strategies for Engineered Negligible Senescence, for example. There were even a few early, unsuccessful efforts to provide technology demonstrations of approaches to break down lipofuscin, or at least some of its components. Unfortunately, getting rid of lipofuscin isn't a straightforward task. Chemically it is diverse, a mess of many very different molecules, and thus ill suited as a target for the enzyme, antibody, and small molecule development that dominates the field of medical biotechnology. Getting rid of one specific molecule is feasible, getting rid of a hundred very different molecules is much less feasible. Lipofuscin has been largely left alone in favor of easier goals.

In today's open access paper, the authors restate some of the arguments for lipofuscin to be important in the onset and progression of age-related neurodegenerative conditions, and thus to be a therapeutic target worthy of greater attention on the part of the research and development community. This has all been said before! One of the challenges inherent to the development of rejuvenation therapies at this stage of the growth of the field is that there are far more potentially worthwhile areas of focus than there are research groups, companies, and funding to carry out the work. This will likely remain the case until the first generation of therapies to treat aging are approved, widely used in the clinic, and their existence a matter of fact for the average physician, researcher, and person in the street.

Lipofuscin accumulation in aging and neurodegeneration: a potential "timebomb" overlooked in Alzheimer's disease

Lipofuscin, which has long been considered a passive byproduct of aging, is increasingly being recognized as a dynamic modulator of cellular homeostasis. Lipofuscin accumulation is indicative of lysosomal dysfunction and is closely related to redox imbalance and lipid peroxidation - critical pathways implicated in neurodegenerative diseases, particularly Alzheimer's disease (AD). Lipofuscin accumulation may contribute to and exacerbate amyloid-β accumulation and toxicity by interfering with autophagic clearance and promoting a highly oxidative environment.

In this review, we propose a reconsideration of lipofuscin from the "aging marker" or "autofluorescence pigment" to an active player in neurodegeneration and AD pathology. This paradigm shift opens new research directions and therapeutic possibilities. Targeting lipofuscin and its clearance may allow interference of upstream of amyloid plaque formation, preserving proteostasis, reducing oxidative damage, and ultimately slowing or preventing neurodegeneration.

We examine the potential interplay between lipofuscin accumulation, lysosomal dysfunction, lipid peroxidation and amyloid-β pathology in AD. We explore how lipofuscin may influence amyloid-β aggregation, clearance, and toxicity and propose mechanisms by which lipofuscin modulates AD progression. Importantly, we summarize evidence demonstrating that lipofuscin is released extracellularly upon neuronal death, thus preparing a highly oxidized environment that results in toxicity and a cascade of events leading to plaque formation and amyloid-β pathology.

A new study proposes a novel approach to fighting immune system decline caused by thymic involution: making the liver produce proteins that support T cell development and function [1].

Bringing back the Ts

Immunosenescence, the gradual deterioration of the immune system, is a central aspect of aging. Research has tied it to increased cancer incidence, vulnerability to infections, weak vaccine responses, and so on [2]. Learning how to keep the immune system active and functional would be a huge leap towards meaningful life extension, although some recent studies suggest this would require simultaneously curbing autoimmunity, which also increases with age.

T cells, an important part of the immune system, mature in the thymus, a small organ near the heart. With age, the thymus experiences involution: the functional tissue gets replaced by fat, and the output falls dramatically. This leads to a loss of naive T cells, which are ready to be primed against a specific new pathoges, and a rise in memory and exhaustion-like T cell states, reducing immune resilience [3].

A new study by MIT researchers, published in Nature, suggests a novel approach to solving this problem. “Efforts to counter immune ageing have primarily focused on reversing thymic involution through hormones, cytokines, small molecules and heterochronic parabiosis, or by directly modulating haematopoiesis,” the paper says. “Although these strategies have provided valuable insights into immune ageing, they have been limited by effect size, toxicity or clinical feasibility.”

Instead of trying to rebuild the thymus, the team used the liver to produce factors that are usually made in the thymus and are central to T cell development.

“If we can restore something essential like the immune system, hopefully we can help people stay free of disease for a longer span of their life,” said Feng Zhang, the James and Patricia Poitras Professor of Neuroscience at MIT, who has joint appointments in the departments of Brain and Cognitive Sciences and Biological Engineering.

Increased thymic output

The authors first tried to pin down which thymic support signals actually fade with age. They profiled thymus tissue across many ages and used spatial assays to study cell–cell communication between thymocytes (immune cells maturing in the thymus) and thymic epithelial cells (TECs). The analysis pointed to age-linked weakening of Notch1/3 and IL-7 signaling programs, alongside reduced interstitial FLT3-L in aged thymus and classic involution metrics, such as a decrease in thymus weight.

Based on these findings, the researchers decided to put back the Notch ligand DLL1 in aged hosts along with FLT3-L and IL-7 to create a combined DFI treatment. They focused on the liver, because its protein-synthesis capacity is preserved at advanced ages and blood circulation, including T cells, passes through it.

The team used mRNA encapsulated in lipid nanoparticles (LNPs) to deliver “production instructions” to the liver, rather than simply flooding the blood with recombinant proteins. This was done for several reasons, including the rapid clearance of recombinant cytokines, toxicity issues associated with frequent dosing, and the fact that Notch ligands are transmembrane and normally require cell-cell contact. This means that simply putting them in the blood would not do the trick, as they must be expressed by cells on their surface, which hepatocytes can do.

The four-week DFI treatment of aged mice (~18 months) increased naive T cell counts and improved the naive-to-memory T cell ratio. Crucially, the team showed that these new cells were not just clones of a few old ones (“peripheral expansion”). Analysis of T cell receptor sequences instead supported the idea that more new T cells are being produced, signifying increased thymic output. None of the three factors alone showed the same effect.

Testing the concept

To determine if this actually makes the immune system work better, the researchers used a vaccination model based on ovalbumin, a harmless protein that the immune system can be primed against as if it were a pathogen. Aged mice normally generate fewer antigen-specific CD8+ T cells and show weaker vaccine responses.

Preconditioning with the DFI treatment improved vaccine-induced T cell responses in aged mice, increasing ovalbumin-specific CD8+ T cells significantly. It also preserved a higher naive T cell fraction post-vaccination, supporting more functional immunity.

Then came the big test: cancer. The team challenged aged mice with melanoma (B16-OVA) or colon carcinoma (MC38-OVA) cells and examined how well older animals could control tumors, including in the context of anti-PD-L1 checkpoint blockade, a current state-of-the-art immunotherapy. As expected, aged mice had faster tumor progression and worse survival, and PD-L1 blockade that controlled tumors in adults had little effect in aged cohorts.

In the melanoma model, DFI pre-treatment followed by anti-PD-L1 drove complete rejection in 40% of aged mice, while all controls died within about 3 weeks. In the colon carcinoma model, DFI pre-conditioning (with a short washout) improved endogenous tumor control, increasing spontaneous rejection rates and prolonging survival. In follow-up profiling, DFI was associated with a higher fraction of intratumoral CD8+ T cells and lower expression of exhaustion-associated markers.

Finally, the researchers checked whether DFI might increase autoimmunity. In a mouse model of type 1 diabetes, an autoimmune disease in which the immune system attacks beta cells in the pancreas, DFI didn’t raise blood sugar or make diabetes start sooner, and it didn’t increase self-reactive T cells. The team then ran tests in two additional autoimmunity models, supporting DFI’s immunological safety in those settings.

Literature

[1] Friedrich, M. J., Pham, J., Tian, J., Chen, H., Huang, J., Kehl, N., … & Zhang, F. (2025). Transient hepatic reconstitution of trophic factors enhances aged immunity. Nature, 1-9.

[2] Liu, Z., Liang, Q., et al. (2023). Immunosenescence: Molecular mechanisms and diseases. Signal Transduction and Targeted Therapy, 8(1), 200.

[3] Liang, Z., et al. (2022). Age-related thymic involution: Mechanisms and functional impact. Aging Cell, 21(8)

Biological age as a concept is a measure of the burden of cell and tissue damage, and consequent dysfunction, that causes risk of mortality and disease. Over the past twenty years researchers have developed a range of approaches, starting with epigenetic clocks, that are attempts to produce a useful measure of biological age. There is considerable debate over the degree to which any of these approaches have succeeded, a debate that will only be settled by the accumulation of a great deal of human data. Ultimately, the real utility of a measure of biological age is the rapid assessment of potential rejuvenation therapies, to steer development towards better approaches that produce larger effects. At present it is unclear as to whether any of the approaches can be trusted to produce useful data given an entirely novel approach to the treatment of aging.

Numerous studies have analysed different aspects of biological age and developed clocks and models to assess biological age and measure the molecular changes due to biological ageing. Not only are there several generations of epigenetic clocks used to estimate biological age, but proteome-based clocks were developed, and metabolome- and microbiome-based clocks are being developed as well. Genomic studies have uncovered several genetic mechanisms that promote longevity, with a focus on protective mechanisms such as protective genetic variants and effective DNA repair systems.

Epigenomic changes that influence biological age are modified by diet and exercise and influenced by early life events. Age-related changes in blood proteome were identified, revealing non-linear and organ-specific alterations. Metabolomic profiles in blood plasma have identified age-related shifts in lipid metabolism and redox balance and demonstrated their application as biomarkers for ageing processes and health outcomes. Microbiomics has shown that the uniqueness and diversity of the gut microbiome reflect biological age and that this can also be measured by microbiome derived metabolites in plasma. In addition, multi-omics approaches have uncovered potential biomarkers that not only reflect the ageing processes but can also serve as targets for personalised interventions.

There are several limitations in selecting reliable biomarkers of ageing. First, there is a lack of consistently identified biomarkers, low methodological standardisation, and limited numbers of cohorts in ageing studies. Currently, ageing appears to be a non-linear process that does not progress at the same rate across all biological functions and organs. Comparisons of different clocks and omics data have shown poor correlation, suggesting that each clock or omics may represent a distinct ageing process. There is limited translation of DNA methylation and other biomarkers into clinical practice.

Furthermore, the definition of biological ageing is not yet clearly established within the community. Therefore, relying on only one type of data is unlikely to provide precise, specific, and reliable biomarkers. Ageing is a systems-level biological process, and only systems-level approaches are likely to lead to the development of reliable and interpretable predictions of biological age. Comparison of different omics data has also shown poor correlation between different molecular domains, indicating that each domain may reflect a different ageing process or organ. Moreover, it is clear that individuals and their organs age differently and at different rates.

Link: https://doi.org/10.1016/j.arr.2025.102988

The research community has achieved a growing ability to engineer bacteria to produce specific behaviors and outcomes. In the realm of cancer therapy, this includes altering the characteristics of bacteria to increase their ability to disrupt cancer cells by preferentially localizing to and colonizing tumor tissue. Techniques demonstrated in the laboratory include genetic engineering of bacteria manufacture or carry a payload of molecules capable of directly harming cancerous cells. The review noted here outlines the range of present approaches, including those that are progressing towards clinical use.

In contrast to conventional drugs, which accumulate through passive diffusion, live bacteria can actively penetrate deep into tumors, bypassing aggregation near blood vessels. The unique properties of the tumor microenvironment (TME) allow bacteria to preferentially replicate and colonize tumors. For example, Salmonella has been observed to localize to tumors at more than 10,000 times the density found in normal tissues. Live bacteria offer distinct advantages over traditional anticancer agents by amplifying antitumor effects through inherent tumor-targeting capabilities, potentially enhancing specific immune recognition. However, balancing the requirement for bacteria to evade host antimicrobial defenses while stimulating antitumor immunity within the TME remains a challenge.

Advances in synthetic biology allow the rational design of optimized oncolytic bacterial strains by attenuating virulence factors and integrating customizable therapeutic payloads, with several candidates already progressing into clinical evaluation. Fine-tuning the spatiotemporal control of bacterial therapeutic activity is essential for maximizing drug accumulation, improving resource efficiency, and reducing harm to healthy tissues. To this end, engineered oncolytic bacteria often utilize regulated gene expression systems, incorporating specific promoter elements, to allow for precise control of therapeutic payload delivery in vivo. Synthetic biology prioritizes rational and modular design, integrating programmable sensors, genetic circuits, and effectors to deliver precise, tunable, multilayer regulation of bacterial behaviors and therapeutic outputs.

Link: https://doi.org/10.1093/procel/pwaf085