LongeCityNews Last Updated: 18 December 2025 - 08:43 PM

In Nature Aging, researchers have discovered how growth differentiation factor 3 (GDF3), a cytokine that increases with aging, is related to more inflammatory macrophages in older animals.

Fat and inflammation

We have recently reported on a potential treatment for visceral fat, as this kind of fat is known to generate health problems, including an increase in inflammation [1]. Macrophages are the cause of some of this inflammation, which also makes fat loss more difficult; this effect has been linked to the GDF3 signaling axis [2].

GDF3 has been heavily studied in multiple contexts, including aging. Unsurprisingly, other research has linked it to fat gain [3], but it has also been found to be effective against blood sepsis [4] and even encourages muscle regeneration in older organisms [5]. As a member of the TGF-β superfamily, it acts on SMAD, a group of molecules that modify gene expression and help to manage chromatin [6], which governs the availability of DNA.

GDF3 changes toxic shock response

In their first experiment, the researchers challenged young and old mice with lipopolysaccharide (LPS), a toxic compound that encourages inflammation. Unsurprisingly, the old mice reacted more strongly than the younger mice, reducing their body temperatures and increasing their numbers of inflammatory macrophages compared to other macrophage types. Gdf3, correspondingly, also substantially increased in the older mice.

The researchers then created a breed of mice that don’t express Gdf3. These mice had few differences from their unmodified counterparts, including in adipocytes, and there were no changes in metabolism. However, among older animals, their numbers of inflammatory macrophages were significantly lower than those of wild-type mice, and they did not have the inflammatory phenotype that makes fat burning difficult. Old Gdf3-knockout mice also appeared to have healthier responses to LPS than old wild-type mice; younger mice saw no benefit.

Animals that had Gdf3 knocked out of only their bone marrow (myeloid) cells had significant reductions in multiple inflammatory factors, including IL-1b and IL-6. In old age, these animals also had significant improvements in glucose metabolism, a better ability to burn fat, and less strong reactions to LPS.

The researchers then attempted to treat GDF3 in older mice by using JQ1 to inhibit BDF4, which binds to GDF3. Older mice treated with JQ1 did not develop hypothermia upon LPS injection the way younger mice did, and they had fewer inflammatory macrophages. These results suggest that GDF3 is treatable.

Changing what genes are accessible

These results were found to be directly related to SMAD. Increasing GDF3 levels also increased the phosphorlyzation of SMAD2/3, which was found to lead to the increased inflammation in macrophages. The researchers confirmed this by directly suppressing SMAD3, which stopped the negative effects of GDF3 in the macrophages of old mice but did not affect younger mice. This suppression also inhibited other gene expressions in young mice, but those effects were not found in the older mice, leading the researchers to conclude that SMAD3, and GDF3, affect different pathways with aging.

Further work found that chromatin remodeling was a significant part of this change. Comparing old murine macrophages with and without Gdf3 revealed significant differences in these cells’ chromatin, which significantly altered which genes were accessible. Not only was there a significant decrease in chromatin-related inflammation in the Gdf3-knockout group, there was significant overlap between genetic pathways that were more accessible in the Gdf3-expressing macrophages and genetic pathways related to aging.

The researchers admit their study’s limitations, most notably that this research only involved mice and murine cells, with no human cells being used. Additionally, GDF3 serves vital biological functions, including in the immune system, and its effects on human beings may be different from those on lab mice kept in a controlled environment. Further work will determine if people have the same age-related changes in GDF3/SMAD function as mice do, along with whether or not this compound can be targeted to fight inflammaging and help people live longer.

Literature

[1] Carey, A., Nguyen, K., Kandikonda, P., Kruglov, V., Bradley, C., Dahlquist, K. J., … & Camell, C. D. (2024). Age-associated accumulation of B cells promotes macrophage inflammation and inhibits lipolysis in adipose tissue during sepsis. Cell reports, 43(3).

[2] Camell, C. D., Sander, J., Spadaro, O., Lee, A., Nguyen, K. Y., Wing, A., … & Dixit, V. D. (2017). Inflammasome-driven catecholamine catabolism in macrophages blunts lipolysis during ageing. Nature, 550(7674), 119-123.

[3] Wang, W., Yang, Y., Meng, Y., & Shi, Y. (2004). GDF-3 is an adipogenic cytokine under high fat dietary condition. Biochemical and biophysical research communications, 321(4), 1024-1031.

[4] Wang, P., Mu, X., Zhao, H., Li, Y., Wang, L., Wolfe, V., … & Fan, G. C. (2021). Administration of GDF3 into septic mice improves survival via enhancing LXRα-mediated macrophage phagocytosis. Frontiers in immunology, 12, 647070.

[5] Patsalos, A., Simandi, Z., Hays, T. T., Peloquin, M., Hajian, M., Restrepo, I., … & Nagy, L. (2018). In vivo GDF3 administration abrogates aging related muscle regeneration delay following acute sterile injury. Aging cell, 17(5), e12815.

[6] Bertero, A., Brown, S., Madrigal, P., Osnato, A., Ortmann, D., Yiangou, L., … & Vallier, L. (2018). The SMAD2/3 interactome reveals that TGFβ controls m6A mRNA methylation in pluripotency. Nature, 555(7695), 256-259.

Mitochondria retain a circular genome distinct from the DNA of the cell nucleus, a legacy of their distant evolutionary origins as symbiotic bacteria. Mitochondrial DNA damage is thought to contribute to the characteristic mitochondrial dysfunction of aging, although the relative contributions of mitochondrial DNA damage versus epigenetic changes in the nucleus that disrupt mitochondrial function remain up for debate. Researchers here provide evidence for a novel form of molecular damage to mitochondrial DNA to contribute to mitochondrial dysfunction. Once again, the question of relative contributions arises, always a challenge in everything associated with mechanisms of aging.

Mitochondrial DNA (mtDNA) is crucial for cellular energy production, metabolism, and signaling. Its dysfunction is implicated in various diseases, including mitochondrial disorders, neurodegeneration, and diabetes. mtDNA is susceptible to damage by endogenous and environmental factors; however, unlike nuclear DNA (nDNA), mtDNA lesions do not necessarily lead to an increased mutation load in mtDNA. Instead, mtDNA lesions have been implicated in innate immunity and inflammation.

Here, we report a type of mtDNA damage: glutathionylated DNA (GSH-DNA) adducts. These adducts are formed from abasic (AP) sites, key intermediates in base excision repair, or from alkylation DNA damage. Using mass spectrometry, we quantified the GSH-DNA lesion in both nDNA and mtDNA and found its significant accumulation in mtDNA of two different human cell lines, with levels one or two orders of magnitude higher than in nDNA.

The formation of GSH-DNA adducts is influenced by TFAM and polyamines, and their levels are regulated by repair enzymes AP endonuclease 1 (APE1) and tyrosyl-DNA phosphodiesterase 1 (TDP1). The accumulation of GSH-DNA adducts is associated with the downregulation of several ribosomal and complex I subunit proteins and the upregulation of proteins related to redox balance and mitochondrial dynamics. Molecular dynamics (MD) simulations revealed that the GSH-DNA lesion stabilizes the TFAM-DNA binding, suggesting shielding effects from mtDNA transactions.

Collectively, this study provides critical insights into the formation, regulation, and biological effects of GSH-DNA adducts in mtDNA. Our findings underscore the importance of understanding how these lesions may contribute to innate immunity and inflammation.

Link: https://doi.org/10.1073/pnas.2509312122

One can debate aspects of the way in which researchers here model what might happen if all of aging is controlled except random mutational damage to nuclear DNA, but the idea is an interesting one. Will random mutational damage to somatic cells be so much harder to eliminate than other aspects of aging that we should think ahead in this way? In tissues where cells are largely replaced, we might think that stem cell populations can at some point be repaired or replaced, and thus the mutational burden in tissues can be reduced over time via the influx of less damaged somatic cells created by the rejuvenated stem cell population. Most neurons in the central nervous system are long-lived, however, and are never replaced. We would have to postulate some very advanced technology to think that we will be able to address the stochastic mutational burden of vital cells in the brain, that damage different in every cell.

Somatic mutations accumulate with age and can cause cell death, but their quantitative contribution to limiting human lifespan remains unclear. We developed an incremental modeling framework that progressively incorporates factors contributing to aging into a model of population survival dynamics, which we used to estimate lifespan limits if all aging hallmarks were eliminated except somatic mutations.

Our analysis reveals fundamental asymmetry across organs: post-mitotic cells such as neurons and cardiomyocytes act as critical longevity bottlenecks, with somatic mutations reducing median lifespan from a theoretical non-aging baseline of 430 years to 169 years. In contrast, proliferating tissues like liver maintain functionality for thousands of years through cellular replacement, effectively neutralizing mutation-driven decline.

Multi-organ integration predicts median lifespans of 134-170 years - approximately twice current human longevity. This substantial yet incomplete reduction indicates that somatic mutations significantly drive aging but cannot alone account for observed mortality, implying comparable contributions from other hallmarks.

Link: https://doi.org/10.1101/2025.11.23.689982

Alzheimer's disease is the most prominent of the tauopathies. This is a class of neurodegenerative conditions in which large enough amounts of tau protein become excessively altered by phosphorylation and aggregate into solid deposits, causing inflammation, loss of function, and cell death in the brain. The various isoforms of tau play an important role in maintaining the structure of axons that connect neurons, but aggregation would be problematic regardless of the normal function of tau.

Just as much of Alzheimer's research and development has long focused on trying to prevent, clear, or disarm misfolded amyloid-β and its toxic aggregates, a similar range of efforts is focused on finding ways to prevent, clear, or disarm hyperphosphorylated tau and its aggregates. Progress to date has been frustrating slow, just as it was for amyloid-β clearance via immunotherapy. Many of the possible paths forward appear challenging to implement well.

Today's research materials present an example of the type, an approach that potentially allows dramatic reduction in overall tau levels. Yet tau is important to axonal function, one can't just get rid of it, which presents developers with the much harder goal of achieving a balancing act with dose and outcome. Even then it tends to be the case that therapies that treat a condition in which a protein becomes altered into a toxic form by reducing overall expression of that protein tend to have unpleasant side-effects.

Novel discovery reveals how brain protein OTULIN controls tau expression and could transform Alzheimer's treatment

The research team initially hypothesized that inhibiting the enzyme activity of the OTULIN protein would enhance tau clearance through cellular garbage disposal systems. However, when they completely knocked out the OTULIN gene in neurons, tau disappeared entirely - not because it was being degraded faster, but because it wasn't being made at all. "This was a paradigm shift in our thinking. We found that OTULIN deficiency causes tau messenger RNA to vanish, along with massive changes in how the cell processes RNA and controls gene expression."

The study used neurons derived from a patient with late-onset sporadic Alzheimer's disease, which showed elevated levels of both OTULIN protein and phosphorylated tau compared to healthy control neurons. This correlation suggested OTULIN might be contributing to disease progression. "OTULIN could serve as a novel drug target, but our findings suggest we need to modulate its activity carefully rather than eliminate it completely. Complete loss causes widespread changes in cellular RNA metabolism that could have unintended consequences."

The deubiquitinase OTULIN regulates tau expression and RNA metabolism in neurons

The degradation of aggregation-prone tau is regulated by the ubiquitin-proteasome system and autophagy, which are impaired in Alzheimer's disease (AD) and related dementias (ADRD), causing tau aggregation. Protein ubiquitination, with its linkage specificity determines the fate of proteins, which can be either protein degradative or stabilizing signals. While the linear M1-linked ubiquitination on protein aggregates serves as a signaling hub that recruits various ubiquitin-binding proteins for the coordinated actions of protein aggregate turnover and inflammatory nuclear factor-kappa B (NF-κB) activation, the deubiquitinase OTULIN counteracts the M1-linked ubiquitin signaling. However, the exact role of OTULIN in neurons and tau aggregates clearance in AD are unknown.

Based on our quantitative bulk RNA sequencing analysis of human induced pluripotent stem cell-derived neurons (iPSNs) from an individual with late-onset sporadic AD (sAD2.1), a downregulation of the ubiquitin ligase activating factors (MAGE-A2/MAGE-A2B/MAGE-H1) and OTULIN long noncoding RNA (OTULIN lncRNA) was observed compared to healthy control iPSNs. The downregulated OTULIN lncRNA is concurrently associated with increased levels of OTULIN protein and phosphorylated tau.

Inhibiting the deubiquitinase activity of OTULIN with a small molecule UC495 reduced the phosphorylated tau in iPSNs and SH-SY5Y cells, whereas the CRISPR-Cas9-mediated OTULIN gene knockout (KO) in sAD2.1 iPSNs decreased both the total and phosphorylated tau levels. CRISPR-Cas9-mediated OTULIN KO in SH-SY5Y resulted in a complete loss of tau at both mRNA and protein levels, and increased levels of polyubiquitinated proteins, which are being degraded by the proteasome. In addition, SH-SY5Y OTULIN KO cells showed downregulation of various genes associated with inflammation, autophagy, ubiquitin-proteasome system, and the linear ubiquitin assembly complex that consequently may prevent development of an autoinflammation in the absence of OTULIN gene in neurons.

Together, our results suggest, for the first time, a noncanonical role for OTULIN in regulating gene expression and RNA metabolism, which may have a significant pathogenic role in exacerbating tau aggregation in neurons. Thus, OTULIN could be a novel potential therapeutic target for AD and ADRD.