Any reasonably complete list of contributions to age-related inflammation is much longer than the few high points noted above. Comprehensively dealing with the inflammation of old age is a task that will require more than one therapy, if the objective is to remove the causes. This is perhaps why much of medical research tends to favor sabotaging inflammatory signaling or aspects of immune cell function rather than addressing causes. It is a bad long term strategy from the point of view of achieving radically better human health, but it works in the short term to get drugs approved and investors their profits. The therapy that is the subject of today's open access report on its initial clinical trial results is an example of the dominant class of approach to chronic inflammation - find a central mechanism involved in coordinating the inflammatory response, and sabotage it. Unfortunately the initial data suggests that this particular anti-inflammatory therapy may not work as well in humans as it does in mouse models of inflammatory neurodegeneration.

Immunotherapy with a short-lived anti-PD-L1 antibody in Alzheimer's disease: a phase 1b, randomized, double-blind trial

While Alzheimer's disease (AD) is initiated by amyloid plaque accumulation, its progression involves local neuroinflammation that the brain cannot resolve when age-related dysfunction of the systemic immune system limits peripheral immune support. Preclinical studies using rodent models showed that transient systemic blockade of programmed death-ligand 1 is associated with reduced neuroinflammation, neuroprotection and attenuation of disease progression. Based on the underlying mechanism, a new short-lived anti-programmed death-ligand 1 antibody with fragment crystallizable (Fc) region-effector silencing and reduced neonatal fragment crystallizable receptor (FcRn) binding (IBC-Ab002) was engineered.

Here, we report a randomized, double-blind, phase 1b first-in-human trial in early AD, with safety and tolerability as the primary endpoint. Forty participants were enrolled across five ascending dose cohorts (1 mg/kg to 30 mg/kg), with dosing administered four times at 3-month intervals. Treatment was well tolerated, with no treatment-related serious adverse events or evidence of amyloid-related imaging abnormalities. Exploratory analyses at week 48 showed directional changes in cerebrospinal fluid biomarkers of neuronal and synaptic damage favoring the 30 mg/kg dose, although no doses reached statistical significance given the limited sample size. The safety and tolerability profile supports further clinical development of systemic, intermittently administered IBC-Ab002 in early AD.

A problem of great complexity

A familiar puzzle in geroscience is that while many of the same longevity-related pathways are highly evolutionarily conserved, manipulating them can produce enormous lifespan gains in simple organisms, such as worms, but much smaller gains in mammals. For instance, a daf-2 mutation can roughly double the lifespan of the nematode worm C. elegans [2], whereas even rapamycin, considered a particularly successful longevity drug, generally produces much more modest effects in mice [2]. There seems to be an additional gap between mice and humans.

This apparent “law of diminishing returns” has frustrated geroscientists for decades. A new study by a European team led by researchers in Romania and Germany, and published in Mechanisms of Ageing and Development, proposes a framework to explain the phenomenon.

The authors first argue that there is a broad inverse relationship between organismal complexity and the size of lifespan extension produced by longevity interventions. In worms, changing one important node can reorganize a large fraction of the organism’s physiology. In Drosophila, the same pathways remain important, but effects are typically smaller and more conditional.

Mammalian lifespan is even harder to extend. For example, rapamycin in mice extends lifespan by around 10-25%, while caloric restriction has substantial but variable effects. Other compounds often improve health or particular aging phenotypes (“healthspan”) without comparably large extensions of maximal lifespan.

From simple pathways to huge networks

The rest of the paper attempts to explain this observation. First, according to the authors, increasing network complexity makes individual pathways less dominant. As biological networks acquire more cross-talk, redundancy, and feedback, perturbing one component produces less change in the overall system (the fraction of the total “aging system” controlled by the intervention’s target shrinks).

For instance, in the worm, pathways such as the insulin/insulin-like growth factor-1 signaling pathway (IIS), mTOR, and DAF-16/FOXO exert a lot of influence. Changing one produces organism-wide effects. In flies, those pathways interact more extensively with mitochondrial metabolism, reproductive signaling, dietary inputs, and stress responses. As a result, the effect of altering TOR, for example, is much more context-dependent.

In mammals, these pathways exist within even larger networks distributed among many tissues. mTOR inhibition is again the authors’ main example: it can produce beneficial effects, but it can also trigger compensatory changes in upstream insulin signaling and has different consequences in different tissues. In other words, the mammalian response to an intervention is partly a response against that intervention, as feedback and parallel pathways work to maintain stability.

That stability is, in fact, useful: a robust, long-lived organism should not have its entire metabolic state transformed whenever one signaling protein changes slightly. However, the very same robustness becomes a problem if the goal is to affect aging.

Specialized tissues and weak links

Next, the authors discuss tissue specialization. As organisms become more complex, aging stops being a mostly cell-intrinsic phenomenon. Instead, the same pathway can have different functions in different tissues. Inhibiting mTOR might be beneficial in one organ but interfere with repair or metabolism somewhere else. Moreover, improving one tissue does not necessarily move the entire organism toward rejuvenation. Recent research into organ-specific aging lends some support to this idea.

Complexity might also explain the “next weakest link effect,” where even if you successfully eliminate one major cause of aging-related death, another failure mode becomes limiting. The most well-known example is the calculation that eliminating cancer mortality altogether would only extend human life expectancy by about three years [4].

Moreover, complexity also means that many effects can be both good and bad (pleiotropic). For instance, growth pathways such as mTOR and IIS support cell proliferation – but sustained proliferative capacity can also drive cancer. Suppressing those pathways may reduce cancer and other hyperfunction-related damage while simultaneously compromising wound healing, immune activity, or regenerative capacity.

Likewise, chronic immune activation contributes to inflammaging and tissue damage, but suppressing immunity too much has its own dangers: cancer and acute infections, both major causes of age-related mortality. Maintaining highly proliferative stem-cell pools would aid tissue repair, but excessive or poorly controlled proliferation increases dysplasia and cancer risk.

Wait, the system is buffering

Organisms have finite resources that can broadly be allocated among growth, reproduction, and somatic maintenance. The authors argue that simple organisms can shift this allocation much more dramatically.

For instance, if food becomes scarce, a worm can substantially downregulate growth and reproduction and upregulate maintenance. Much of the extraordinary lifespan extension from dietary restriction or mutations in related pathways may represent this fundamental switching into a different life-history state. Flies retain this ability to some extent; for instance, amino-acid restriction can reduce reproductive investment and increase lifespan.

Mammals, on the other hand, have expensive specialized organs and tissues and rigid physiological commitments, meaning they cannot just redirect a huge fraction of their resources from one biological program and to maintenance without disrupting essential functions. Consequently, caloric restriction can still shift mammalian physiology toward maintenance, but to a lesser degree.

All these arguments are ultimately folded into one conceptual principle: maximum lifespan extension is proportional to pathway leverage divided by system buffering. As complexity rises, pathway leverage declines because aging control becomes distributed among more pathways, tissues, and physiological systems, while system buffering increases as redundancy, feedback, tissue interactions, and compensatory mechanisms become stronger. The predicted result is a decline in the maximum possible effect from a single intervention.

While this framework explains some observations, it remains mostly theoretical. However, if the authors are correct, meaningful human lifespan extension will probably require multi-target, multi-tissue interventions rather than finding one molecular “master switch.”

Literature

[1] Pirscoveanu, D. F., Papa, M. C., Kaltwasser, B., Hermann, D. M., Brockmeier, U., Cercel, A., … & Popa-Wagner, A. (2026). Biological limits of lifespan extension: evidence for a shift from pathway leverage to system-level buffering across species. Mechanisms of Ageing and Development, 112231.

[2] Kenyon, C., Chang, J., Gensch, E., Rudner, A., & Tabtiang, R. (1993). A C. elegans mutant that lives twice as long as wild type. Nature, 366(6454), 461-464.

[3] Harrison, D. E., Strong, R., Sharp, Z. D., Nelson, J. F., Astle, C. M., Flurkey, K., … & Miller, R. A. (2009). Rapamycin fed late in life extends lifespan in genetically heterogeneous mice. Nature, 460(7253), 392-395.

[4] Yashin, A. I., Ukraintseva, S. V., Akushevich, I. V., Arbeev, K. G., Kulminski, A., & Akushevich, L. (2009). Trade-off between cancer and aging: what role do other diseases play?: evidence from experimental and human population studies. Mechanisms of ageing and development, 130(1-2), 98-104.

Mitochondrial transplantation has emerged as a promising strategy for modulating cellular bioenergetics in mitochondrial dysfunction. However, isolated mitochondria suffer from poor stability and limited cellular uptake, restricting their therapeutic application. To address these limitations, we developed a surface engineering strategy that stabilizes isolated mitochondria while enabling interactions with target cells, providing a platform for selective organ- and cell-targeting. Polyethylene glycol (PEG) with lipid/carbon chains was introduced to mitochondria-associated membrane structures, forming a protective hydration layer on the mitochondrial surface. This PEG layer also serves as a modular platform for functionalization with biomolecules, such as peptides and antibodies, thereby broadening its biomedical applications.

In this study, we examined whether mitochondrial function in target cells can be modulated using PEG-shielded mitochondria functionalized with a cell-penetrating peptide (CPP) via a maleimide linkage. Our results suggest that CPP-PEG-modified mitochondria exhibit efficient cellular internalization and are associated with increased mitochondrial respiratory activity, consistent with intracellular bioenergetic modulation. These findings suggest that spatially controlled presentation of CPP at the terminus of a PEG layer may provide an effective approach for stabilizing isolated mitochondria while modulating intracellular dynamics and functional responses. This surface engineering strategy offers a proof-of-concept design framework for mitochondria-associated engineering and future bioenergetic strategies.

Link: https://doi.org/10.1002/admi.70583

Traditionally, periodontitis was viewed as a simple infection; however, it is now recognized as a complex polymicrobial disease driven by synergistic interactions within the oral microbiota and a subsequent aberrant host immune response. Periodontitis is typically initiated by a shift from symbiotic to dysbiotic microbial communities. In this process, 'keystone pathogens' such as Porphyromonas gingivalis, even at low abundance, can remodel the surrounding commensal bacteria into a highly inflammatory state.

Recently, a new cancer-targeted therapy called near-infrared photoimmunotherapy (NIR-PIT), which combines antibody-dye conjugates and near-infrared light, has emerged. The cell death mechanism of NIR-PIT is unique. Specifically, when the conjugate is irradiated with near-infrared light in the presence of sufficient electron donors, the hydrophilic side chain (silanol) of the IR700 molecule dissociates through a photochemical ligand reaction, and the remaining structure, including the antibody, rapidly becomes hydrophobic and aggregates. At the same time, the antibodies bound to the surface antigens also aggregate on the tumor cell membrane. The aggregation reaction of IR700 causes physical stress on the antigen-antibody complex and selectively destroys the target cells

We recently developed NIR photoantimicrobial-targeted therapy (NIR-PAT2) to treat infectious diseases. For NIR-PAT2, as targeting molecules, we exploit immunoglobulin Y (IgY). NIR-PAT2 with IgY could be used for body surface and lumens, such as skin, hair, eye, digestive tract. The aim of this study was to develop a bacteria-targeted therapeutic modality using NIR-PAT2. While we acknowledge the inherent limitations of single-pathogen targeting in a complex polymicrobial disease, we hypothesized that selectively eliminating a keystone species would disrupt the synergistic drivers of dysbiosis. We define this approach as a precision-modulating therapy, designed to selectively ablate P. gingivalis while preserving the ecological integrity of the oral community. Here, we demonstrate that NIR-PAT2 successfully modulates oral dysbiosis, leading to the resolution of periodontitis and the restoration of a healthy-associated microbial profile in a murine model.

Link: https://doi.org/10.1186/s12967-026-08336-2

Blood pressure is a condition of its own

The authors begin their paper by discussing high blood pressure (hypertension), one of the most commonly known medical issues and a significant contributor to both disability and mortality in older people [1]. Between normal blood pressure (normotension) and hypertension sits prehypertension, an intermediate state that signifies increased risks [2].

Prehypertension often begins when the endothelium, which lines the blood vessels, becomes dysfunctional with aging and various other medical issues [3]. Glucose, lipids, and physical stresses damage these cells [4], leading to senescence, the production of reactive oxygen species (ROS), and vascular aging [5].

Previous work has found that an factor involved in blood vessel creation, AGGF1, may help combat this chain of events by fighting inflammation related to TNF-α [6]. A study from earlier this year found that AGGF1 is repressed in hypertensive patients [7]. Therefore, this study aimed to discover its precise role in preserving the endothelium and determine whether or not it is a potentially valuable target.

AGGF1 has significant effects on blood pressure

This study began with a look at data derived from the Gene Expression Omnibus database, which is commonly used in analyses like this one. Unsurprisingly, AGGF1 was found to significantly decline with both hypertension and aging.

The researchers then turned to mice, which have age-related hypertension issues just like we do [8]. They employed two male mouse models: one that fails to express murine Aggf1, and one that overexpresses human AGGF1. A control group of wild-type Black 6 mice maintained normal blood pressure at 18 months; the underexpressing group developed high blood pressure at 11 months; and while overexpression did not stop blood pressure from rising completely, the overexpressing group had considerably less hypertension even at 25 months of age, a statistically significant improvement over the wild-type group.

A closer look revealed this to be entirely due to AGGF1’s effects on the endothelium. Endothelium-dependent forms of blood vessel relaxation were negatively impacted by underexpression and positively affected in older ages by overexpression. Forms of blood vessel relaxation that do not rely on the endothelium were unaffected. AGGF1 was also found to have benefits against ROS production, with overexpressing mice producing significantly less and underexpressing mice producing significantly more.

An analysis of human umbilical vein endothelial cells (HUVECs) found even more effects: endothelial cells that underexpress AGGF1 have more markers of senescence, higher expression of the DNA damage marker γH2AX, increased inflammation as measured by IL-6, and less cellular proliferation. Increasing AGGF1 expression reduced the effectiveness of doxorubicin, a toxin that causes cellular senescence.

An established downstream protein

These results were found to be due to AGGF1’s effects on the expression of SESN2, a protein that has been previously examined in other age-related contexts, including knee arthritis. A database analysis of human expression found that SESN2 and AGGF1 expression are related in older people, and this team found similar results in its mice.

Directly affecting SESN2 overrode the effects of AGGF1 in HUVECs; cells that were forced to express SESN2 without AGGF1 had decreased senescence, but cells that overexpressed AGGF1 without SESN2 had increased senescence. These results were confirmed in mice; administering a SESN2 adeno-associated virus (AAV) to Aggf1-underexpressing mice significantly reduced this group’s tendency to develop high blood pressure at an early age. Likewise, silencing SESN2 in AGGF1-overexpressing mice caused this group to develop high blood pressure earlier.

This study had a few notable limitations: this was murine and cellular work, and only male mice were utilized in this study. The reason why AGGF1 declines with age was not explored. However, this is further evidence of SESN2’s impact on aging tissues, and the researchers claim that these findings “identify the endothelial AGGF1/SESN2/p-eNOS axis as a novel and important signaling pathway in the maintenance of blood pressure.”

Literature

[1] Benetos, A., Petrovic, M., & Strandberg, T. (2019). Hypertension management in older and frail older patients. Circulation research, 124(7), 1045-1060.

[2] Egan, B. M., & Stevens-Fabry, S. (2015). Prehypertension—prevalence, health risks, and management strategies. Nature Reviews Cardiology, 12(5), 289-300.

[3] Zhao, L., Meng, X., Zhang, Q. Y., Dong, X. Q., & Zhou, X. L. (2021). A narrative review of prehypertension and the cardiovascular system: effects and potential pathogenic mechanisms. Annals of Translational Medicine, 9(2), 170.

[4] Zhang, Y., Yang, X., Lan, M., Yuan, Z., Li, S., Liu, Y., … & Li, B. (2025). Regulation of blood pressure by METTL3 via RUNX1b–eNOS pathway in endothelial cells in mice. Cardiovascular Research, 121(1), 205-217.

[5] Ungvari, Z., Tarantini, S., Donato, A. J., Galvan, V., & Csiszar, A. (2018). Mechanisms of vascular aging. Circulation research, 123(7), 849-867.

[6] Hu, F. Y., Wu, C., Li, Y., Xu, K., Wang, W. J., Cao, H., & Tian, X. L. (2013). AGGF1 is a novel anti-inflammatory factor associated with TNF-α-induced endothelial activation. Cellular signalling, 25(8), 1645-1653.

[7] Gao, D., Wu, Z., Zhou, Z., & Liang, J. (2026). BACH1-mediated transcriptional repression of pro-angiogenic factors drives angiogenic impairment in hypertension. Frontiers in Cardiovascular Medicine, 13, 1769747.

[8] Feng, R., Ullah, M., Chen, K., Ali, Q., Lin, Y., & Sun, Z. (2020). Stem cell‐derived extracellular vesicles mitigate ageing‐associated arterial stiffness and hypertension. Journal of extracellular vesicles, 9(1), 1783869.

With age stem cell function declines, reducing the pace at which stem cells deliver replacement somatic cells with long telomeres. As a result, average telomere length falls and the proportion of cells with very short telomeres increases in tissues throughout the body. This has a meaningful negative effect on health, a driver of chronic inflammation, increased numbers of senescent cells, and impaired tissue function. In today's open access paper, researchers report on their efforts to specifically sabotage the cascade of mechanisms that emerge in response to short telomeres in a cell, showing that it improves health in aged mice, at least in the short term. The flip side of the coin, not investigated here, is that this could increase cancer risk by promoting damage to DNA via the continued operation of damaged cells, usually avoided because cells with very short telomeres are destroyed on some timescale.

Therapeutic inhibition of telomeric DNA damage response rescues hematopoietic dysfunction driven by telomere shortening and aging

Telomeres progressively shorten and accumulate damage with aging, and this contributes to cellular senescence and hematopoietic dysfunction. When critically short, telomere ends are detected as DNA damage and trigger a telomeric DNA damage response (tDDR), a signaling cascade involving posttranslational protein modifications, such as phosphorylation of histone H2AX at serine 139 (known as γH2AX), which promotes recruitment of DDR factors including phosphorylated KRAB-associated protein 1 (pKAP1) at damaged sites. Persistent tDDR drives cellular senescence and cell death. The inability of senescent cells to proliferate impairs tissue regeneration, and their secretion of proinflammatory factors, collectively known as the senescence-associated secretory phenotype, promotes chronic, low-grade inflammation, disrupting the local microenvironment and eventually causing systemic frailty.

Whether the tDDR causally impairs hematopoiesis remained unclear. Here we show in telomerase-deficient Telomerase RNA component (TERC) knockout mice, which recapitulate telomere-driven hematopoietic dysfunction and aging, that targeting telomeric noncoding RNAs with telomeric antisense oligonucleotides (tASO) suppresses tDDR in hematopoietic organs, reduces senescence and inflammation, alleviates hematopoietic dysfunction, and enhances hematopoietic stem cell fitness and repopulating potential in vivo. Similar observations were recapitulated in aged wild-type mice, and ex vivo treatment with tASO improved the function of human hematopoietic stem cells from aged donors.

Taken together, our results identify tDDR as a pathogenic driver of hematopoietic decline and support tASO-mediated tDDR inhibition as a potential therapeutic strategy for telomere biology disorders and age-associated hematopoietic aging.