How Immune Function Affects Aging

"Any cell in the body can become senescent, typically when damaged by a mutation. Once in this state, cells start to secrete inflammatory signals, flagging themselves for destruction. This is an important anticancer and wound-healing mechanism that works well in youth. But when too much damage accumulates with ageing — and immune cells themselves also become senescent — the mechanism breaks down. Senescent immune cells, attracted by the inflammatory signals from senescent tissue, secrete their own inflammatory molecules. So not only do they fail to clean up properly, but they also add to the inflammation that damages surrounding healthy tissue. The phenomenon is known as ‘inflammaging’. “It becomes a terrible positive feedback — a never-ending dance of destruction,” says immunologist Arne Akbar at University College London. And evidence suggests that this feedback loop is kicked off by the immune system. In a series of experiments in mice4, Laura Niedernhofer at the University of Minnesota in Minneapolis has shown that immune-cell senescence actually drives senescence in other tissues. “These cells are extremely dangerous,” she says." https://lnkd.in/etkJpDWH

This study finds that a critical immune pathway is linked to a massive 15-year longevity benefit. And yes, there may already be ways to target it. Here, the authors measured multiomics biomarker signatures in 17,500 individuals across various ages, and looked for predictors of immune system resilience, defined as the ability to mount an immune response without causing chronic inflammation. They looked both at predictors of poor immune resilience, and healthy immune resilience (=salutogenic mechanisms). A core network emerged, driven by elevated levels of a protein called TCF1, a master regulator of T-cell function and renewal capacity. Individuals with greater activity in this pathway had: ·        Better immune competence ·        Less chronic inflammation ·        Lower senescent cell burden ·        And a 15-year increase in life expectancy! This study will surely set off a hunt for new interventions that can increase TCF1 levels and activity. In the meantime, we do have hints that some existing longevity interventions could be acting (in part) through this pathway: 💊 In this study, patients receiving TNFα antagonists shifted from a low immune resilience signature to a high one, providing direct evidence that this immune longevity network is responsive to drug interventions. 💊Rapamycin also activates TCF1 in T-cells . This could be responsible for some of the observed benefits of rapa on increasing immune competence and decreasing chronic inflammation. 💊SGLT2 inhibitors, commonly used to lower blood sugar in diabetes and more recently used as longevity agents, decrease GSK3β signaling, which subsequently increases TCF1.   💊Low-dose lithium, which is increasing being recommended for longevity applications, also reduces GSK3β activity, with downstream impacts on TCF1. Expect to hear a lot more about TCF1 in the coming years. This could be a new frontier in immune-based longevity. 📰 Sources in comments. #longevity #aging

Reviving Immunity: The PEPITEM Pathway and Its Promise for Aging The article presents significant findings on rejuvenating leukocyte trafficking in aged mice through PEPITEM intervention. The study explores how the PEPITEM pathway, which regulates leukocyte migration during inflammation, becomes dysfunctional with age and how this supplementation can reverse PEPITEM dysfunction. The researchers used a zymosan-induced peritonitis mouse model to investigate these effects in young (3-month-old) and aged (21-month-old) mice. Key findings from the study include that aging amplifies the inflammatory response, resulting in increased CD45+ leukocytes in the inflamed peritoneum of aged mice. PEPITEM treatment reduced CD45+ leukocyte recruitment in young and old mice, particularly affecting CD4 and CD8 T-cell subsets. The study also noted an increase in terminally differentiated CD3+KLRG1+ T-cells in aged mice, which was inhibited by PEPITEM treatment. Additionally, PEPITEM reduced the infiltration of naive and central memory T-cells in young and old mice but only affected effector memory T-cells in young mice. The research further demonstrated that the PEPITEM pathway is dysfunctional in older adults but can be rescued through PEPITEM supplementation. Molecular analysis revealed lower levels of APPL1, an essential signaling protein, and reduced production of 14-3-3ζ in B-cells from older adults. This explains the loss of response to adiponectin and the dysregulation of lymphocyte transendothelial migration. This research is crucial for the field of anti-aging for several reasons. Firstly, it introduces a novel therapeutic approach with PEPITEM, which not only dampens excessive inflammation but also supports the maintenance of immune homeostasis. Secondly, it suggests that PEPITEM supplementation could rejuvenate immune responses in the aged population, addressing the critical issue of inflammaging. Thirdly, the study provides mechanistic insights into the molecular changes in the adiponectin-PEPITEM pathway with aging, opening new avenues for targeted interventions. Lastly, by potentially enhancing immune function in older adults, this research contributes to the broader goal of improving healthspan alongside increasing lifespan, inspiring and motivating further research in this area. The study represents a significant advancement in understanding immune system aging and offers a promising approach to rejuvenating immune functions in older individuals. The potential of PEPITEM as a powerful geroprotective agent could have far-reaching implications for improving healthspan and addressing age-related inflammatory conditions, instilling hope in anti-aging research. JP https://lnkd.in/e9xzCKBv

What if your brain and immune system are the real keys to longevity? 🔥 Just out in Nature Medicine 🔥 “Plasma proteomics links brain and immune system aging with healthspan and longevity” by Hamilton Se-Hwee Oh, Tony Wyss-Coray, Anne Brunet, Michael Greicius & colleagues We often talk about aging as a slow, systemic decline ; but what if the real story is about a few crucial organs pulling the strings? We've been studying how immune system aging drives systemic decline for almost 2 decades and reading this elegant paper reaffirms this claim. In this massive study of ~45,000 people from the UK Biobank, Tony's group built machine learning models that estimate the biological age of 11 organs from plasma proteins. 🧬 Key insights: ✅ Each organ ages independently —> brain and immune system stand out ✅ Aged brains increase Alzheimer’s risk as much as carrying an APOE4 allele ✅ Aged immune systems drive mortality and chronic diseases ✅ Youthful brains and immune systems reduce mortality risk by nearly 60% ✅ Individuals with both youthful organs had the lowest death risk of all (HR = 0.44) ✅ Plasma proteomics tracks aging better than existing clinical clocks (like PhenoAge) 💡 The promise for longevity: If we can measure, protect, and intervene on the aging of specific organs — especially the brain and immune system — we might delay chronic disease and extend healthspan. Massive kudos to the phenomenal team across Stanford, the UK Biobank Pharma Proteomics Project, and the Wu Tsai Neurosciences Institute for making this possible. A milestone in translational aging science! BRAIN AND IMMUNE SYSTEM YOUTH PREDICT LONGEVITY #longevity #aging #biomarkers #proteomics #brainhealth #immunology

Can we reverse cancer risk by treating chronic inflammation in aging? Dr. Miriam Merad and her team at Mount Sinai think so — and they’re turning conventional wisdom on its head. As 90% of cancers occur in people over 50, Dr. Merad has zeroed in on a surprising culprit: inflammaging — the chronic, pathogenic inflammation that accumulates as we age. Rather than simply “weakening,” the aging immune system may become hyperactive in harmful ways, priming the body for cancer. The approach is groundbreaking: it uses existing anti-inflammatory drugs, from allergy meds to JAK inhibitors, to reduce this background inflammation. In animal models, this strategy slowed tumor growth and, in one case, reversed it when young immune systems were introduced. At Halia Therapeutics, this is precisely the frontier we are exploring. We believe chronic inflammation is not just a byproduct of aging but a modifiable disease driver. Our lead compound, HT-6184, is an oral allosteric inhibitor of Nek7/NLRP3 inflammasome activation — a key source of inflammaging. We’re now advancing this therapy across clinical programs in cancer, obesity, MDS, and Alzheimer’s disease, where inflammation plays a central role. The future of medicine will require revving up the immune system and knowing when to press the brakes. Balancing the immune response, especially in aging, could be one of the most potent ways to prevent or delay chronic disease. https://lnkd.in/gV7WWPsK #Inflammaging #CancerResearch #LongevityScience #Immunology #TechBio #HaliaTherapeutics #NLRP3 #PrecisionMedicine #GoodMedicinePodcast

Sooo, why do we get cancer? Anyone who has had cancer, or a loved one with cancer, has, at one point or another, sat back and quietly asked themself "Why? Why does this happen?" It can be such a mysterious thing. A tumor just sort of comes into existence, spreads all over the body, and then threatens to destroy organ function and kill the person entirely, seemingly out of nowhere... So, what's the deal? Why DO we get cancer? Well, there a lot of reasons, but most people probably think of these two: 1. Long-term exposure to carcinogens - like UV from the sun, tobacco from cigarettes, or asbestos from old flooring or paint - wreak havoc on the DNA, which can result in the acquisition of mutations and oncogenic transformation. 2. More fundamental genetic events like the formation of chromosomal fusions, such as EWS-FLI1 in Ewing's sarcoma, or the inheritance of germline mutations that increase risk of cancer development, like BRCA1/2 mutations in breast and ovarian. However, there is one "cause" of cancer that most people seem to overlook. What is it? "Immunodeficiency" Now, I put it in quotes because immunodeficiency, technically speaking, is not exactly a cause of cancer. For example, if you were to take away my entire immune system, that event on it's own would not CAUSE cancer to form. However, in order for a clinically relevant malignant tumor to form, it must evade your immune system. So, if your immune system is in tip-top shape, tumors have a pretty hard time going unnoticed. However, if your immune system is hanging on by a thread, a malignant lesion has a much easier time breaking the law. As we grow older, our immune system naturally "slows down"; cytotoxic cells lose their proliferative potential, inflammatory immune cell subsets increase, and memory cells decrease. This puts the elderly at increased cancer risk and is one of the reasons why we consider cancer to be a "disease of aging". What if there was a way to rejuvenate an aged immune system? Give it an elixir that healed it's wounds and restored it to it's younger self. Well, Irv Weissman's group at UCSF just did it in a mouse and are most likely now transitioning their findings into human studies... They found that, by inhibiting the differentiation potential of blood stem cells that give rise to inflammatory and immunosuppressive cells (myeloid cells) using various antibodies, you can increase the relative number of lymphocytes (T cells, B cells) that are involved in the adaptive immune system. They were able to convert an "old immune system" into a much "younger" one with a simple antibody treatment. This is potentially revolutionary as it has the potential to significantly alter the progression of diseases that are associated with an aging immune system such as chronic inflammation, vulnerabilities to viral and bacterial infections, and yes, even cancer. I'll link the full article in the comments!