This article concludes our series on the Hallmarks of Aging and on the ways science may be able to influence them. Earlier in the series, we introduced the topic in an overview of the rejuvenation field, and then explored specific mechanisms in articles on genetic and epigenetic changes, protein quality control, mitochondria, and cellular senescence, and autophagy, metabolism, and stem cells. Here we focus on the final three: altered intercellular communication, chronic low-grade inflammation, and dysbiosis.
These processes form an almost self-reinforcing loop, and they also interact with other drivers of aging: dysbiosis can amplify inflammation; chronic inflammation alters signaling between tissues and accelerates the accumulation of senescent cells (which we discussed in more detail earlier); and senescent cells, in turn, release pro-inflammatory signals that help sustain this inflammatory state.
Researchers are already testing interventions in these processes, and in animal studies some of them have extended lifespan or reduced signs of aging. Let’s take a closer look at each of them.
Altered intercellular communication
Cells are in constant communication — through hormones, cytokines (the immune system’s chemical messages), neurotransmitters, extracellular vesicles, and molecules in the extracellular matrix. In a young body, these signals are usually well coordinated: where to grow, where to repair, and where to keep inflammation in check.With age, this communication starts to break down: helpful signals weaken, while danger and inflammatory cues, along with pathways that suppress repair, may remain active even when they are no longer needed.
Once that happens, a localized tissue damage can develop into a systemic problem: regeneration slows, fatigue rises; infection, cold, or injury lower resilience to stress, and gradually metabolism shifts.
This happens for several reasons. With age, some cells enter a state of senescence — they stop dividing but actively secrete pro-inflammatory signals. These signals alter the behavior of neighboring cells and may spread dysfunction through the surrounding tissue. Aging also increases the activity of NF-κB, one of the central regulators of inflammation. That, in turn, activates gene programs associated with aging and accelerates functional decline in tissues. In animal studies, suppressing NF-κB has partially reduced some features of tissue aging.
Blood plasma also contains different mixtures of signaling molecules at different ages, and these circulating factors help shape how tissues function. In mice, researchers saw beneficial effects even without adding “young blood”: simply diluting old plasma with saline and albumin was enough to improve several measures.
Studies have shown that when senescent cells were removed (and, accordingly, the pro-inflammatory factors they secreted were also removed), older mice lived about 36% longer after treatment began.
In another experiment about half of the plasma in mice was replaced with saline containing 5% albumin, and in several tests, the effects matched or even exceeded those seen with exposure to “young blood”: improved muscle repair, reduced fat accumulation and fibrosis in the liver, and increased neurogenesis in the hippocampus.
Chronic inflammation
In aging, chronic inflammation often takes the form of a persistent, low-grade inflammatory state without any obvious infection. It is sometimes called inflammaging.
This persistent inflammatory state increases the risk of many age-related diseases and reduces the body’s physiological reserve. Reviews consistently link inflammaging with higher rates of disease and death in older adults.
Many different processes appear to drive inflammation upward with age.
For example, many “danger signals” — including dying cells, crystals, and metabolic disturbances — can trigger the production of inflammatory molecules. The levels of some pro-inflammatory molecules increase over time in many tissues because of metabolic changes in the body. Inflammation and cellular senescence can also reinforce one another, creating another vicious cycle.
Animal studies have produced some striking results here as well. For example, scientists studied the NLRP3 protein complex, which triggers the inflammatory response in cells. In male mice, deleting NLRP3 increased median lifespan by about 34% and maximum lifespan by 29%, while also reducing signs of cardiac aging at both the functional and molecular levels.
In 2024, Nature published results pointing to an important role for IL-11 — a signaling molecule involved in inflammation and age-related tissue changes.
In mouse experiments, scientists tested two approaches.
First, they genetically switched off the IL-11 gene, and these animals developed fewer age-related metabolic problems and retained better physical fitness.
Second, the researchers administered IL-11-blocking antibodies to older mice (approximately 75 weeks old). The animals showed improved metabolism and muscle strength, and signs of frailty became less pronounced.
In addition, median lifespan increased by about 22.5% in males and 25% in females.
Antibodies against IL-11 are already undergoing early clinical trials in humans for pulmonary fibrosis, which makes this pathway especially interesting as a possible target in aging research.
Dysbiosis: age-related changes in the microbiome
The gut microbiome is a complex ecosystem of microorganisms that helps process food, trains the immune system, and produces metabolites (for example, short-chain fatty acids). With age, the composition of the microbiome often changes: diversity may decline, the proportion of beneficial bacteria may decrease, while opportunistic microbes may become more abundant. These shifts are also heavily influenced by diet, medications, lifestyle, and overall health. On average, the gut microbiota of older adults differs from that of younger people.
Dysbiosis can increase intestinal barrier permeability (“leaky gut”) and trigger systemic inflammation. It can also shift the balance of metabolites, including SCFAs and secondary bile acids, with consequences for metabolism and immune function.
In one study on the relationship between dysbiosis and aging, scientists used killifish — a short-lived vertebrate often used in aging research. In the experiment, middle-aged fish were first given a course of antibiotics to clear much of the existing gut microbiota, and they then received a single transplant of microbiota from young fish. After this procedure, median lifespan increased by about 37% compared with untreated fish, by 41% compared with transplantation from age-matched donors, and by 21% compared with antibiotics alone.
In addition, their behavior and activity levels declined more slowly as well, suggesting a broader slowing of age-related decline.
However, the results have limitations. The antibiotic treatment alone also extended lifespan somewhat (by about 14%), so part of the effect may be related to the removal of harmful bacteria.
In studies of fecal microbiota transplantation (FMT), researchers studied mice with progeroid syndromes — genetic models of accelerated aging.
When such mice received microbiota from healthy wild mice, their health improved and lifespan increased. In one of the models, median lifespan increased from about 160 to 170 days, and maximum lifespan from about 172 to 193 days.
Some of these benefits could even be reproduced with a single bacterial species — Akkermansia muciniphila. Scientists suggest that one possible mechanism is linked to restoration of normal bile acid metabolism, which plays an important role in metabolism and gut function.
However, regulators also point to possible risks of this therapy. For example, the FDA (U.S. Food and Drug Administration) warned about cases of severe infections after microbiota transplantation and introduced additional requirements for thorough donor screening.
Many researchers therefore expect the field to move gradually away from transplanting relatively raw microbiota and toward more controlled approaches — for example, the use of individual bacterial strains, carefully designed microbial consortia, or bacterial metabolites.
Limitations and open questions
Research on aging increasingly shows that its hallmarks are deeply interconnected: acting on one node often changes several others at once. But that does not mean aging will be solved by a single universal “anti-aging pill”. A more realistic picture is one of multiple interventions, each acting on a different part of the aging process.
The central question now is no longer whether these strategies can improve outcomes in model animals, but which of them will prove both effective and safe in humans. To answer this, we need to understand which signals, metabolites, cytokines, extracellular vesicles, and other components are the key nodes of the system, which biomarkers best reflect the body’s biological age, and which combinations of approaches will be able not just to improve individual markers, but to meaningfully extend human healthspan.