If you have ever wondered why the women in your family seem to outlast the men, you are noticing something real. According to the OECD’s Health at a Glance 2025 report, women live longer than men in every OECD country, with an average gap of 5.2 years in 2023 (83.7 years for women versus 78.5 years for men). Yet the same report found that a woman at 60 can expect 3.4 more years than a man, while spending 6.3 of her remaining years with activity limitations and a larger share of her later life in poor health (26% versus 24%). Add to that the NIH Office of Research on Women’s Health’s finding that nearly 80% of people with an autoimmune disease, including lupus and rheumatoid arthritis, are women, and you have a paradox that has puzzled researchers for decades. A study published this August in Nature Communications offers one of the clearest pictures yet of what may be happening, and the answer seems written into our immune cells.
Let me walk you through what the researchers found, what it means for you at different life stages, and then take an honest look at which natural compounds have real human evidence for supporting an aging immune system, and which do not.
First, a Few Terms in Plain Language
Your immune system is not a single thing. It is a team of specialized white blood cells. T cells are the coordinators and the precision fighters. CD4 T cells act like team captains, directing the response, while CD8 T cells seek out and destroy virus-infected or cancerous cells. NK cells, or natural killer cells, are fast first responders that can eliminate abnormal cells without prior instruction.
As we age, this team changes. Scientists call this gradual remodeling immunosenescence, or immune aging. We make fewer fresh, “naive” T cells ready to learn new threats, and we accumulate more experienced, worn-out cells. At the same time, a low, smoldering level of inflammation tends to build up in the body. Researchers call this inflammaging, and a widely cited 2018 review by Franceschi and colleagues in Nature Reviews Endocrinology describes it as chronic, sterile, low-grade inflammation that contributes to many age-related diseases.
It also helps to know that men and women do not start from the same place. A well-known 2016 review by Klein and Flanagan in Nature Reviews Immunology summarized decades of evidence that females generally mount stronger innate and adaptive immune responses than males. That advantage helps clear infections and respond to vaccines, but the same vigor also increases the risk of autoimmunity.
A New Map of Immune Aging
The new study, led by Harry Park and Jacques Behmoaras at Duke-NUS Medical School in Singapore, combined four large datasets to analyze about 3.8 million immune cells from blood (peripheral blood mononuclear cells) from 1,828 healthy people aged 19-97. The group included 1,021 women and 807 men from 12 self-reported ethnic backgrounds, and 34.8% were Asian, which matters because most earlier immune aging research drew heavily on people of European descent.
What makes this work stand out is resolution. Instead of measuring blood as one big mixture, the researchers looked at gene activity cell type by cell type, and they did it separately for women and men.
Two Turning Points: Your 40s and Your 60s
The first big finding is that immune aging is not a slow, steady slope. It comes in waves. The researchers saw two prominent peaks in gene activity: one around age 40, driven mainly by CD4 T cells, and another after age 60, driven mainly by CD8 T cells. These peaks held up when the team changed their analysis settings and disappeared when ages were randomly shuffled, suggesting they aren’t a statistical accident. Interestingly, each individual dataset captured only one of the two peaks. Combining them revealed the full picture.
This lines up with earlier work. In 2020, Márquez and colleagues, also writing in Nature Communications, studied chromatin and gene activity in blood immune cells and found two periods of abrupt immune change across adult life: one in the late thirties to early forties and another later in life.
The Singapore authors point out that the 40s coincide with declining fertility and early hormonal shifts, and the 60s with the years after menopause in women and continued testosterone decline in men. They did not prove that hormones cause the waves, but the timing is hard to ignore.
Across both sexes, the researchers saw a coordinated slowdown in the cell’s protein-making machinery. Genes for ribosomes (the cell’s protein factories), for starting protein production, and for quality control of genetic messages all declined with age. The authors describe this as failed proteostasis, meaning cells become less able to keep their proteins in good working order. Meanwhile, immune activation and inflammatory pathways rose, especially in CD8 T cells, reflecting inflammaging at the gene-activity level. The mix of cells also shifted in both sexes: fewer naive CD8 T cells and fewer protective MAIT cells, with more NK cells, more inflammatory CD16 monocytes, more effector memory CD8 T cells, and more regulatory T cells.
Where Women and Men Part Ways
Here is where the story gets personal. Women showed more pronounced age-related changes overall, with 5,204 age-related gene features in women compared with 4,346 in men, and women consistently showed higher peaks.
Some patterns were shared, but several were unique to one sex. In men, the researchers found an “early fluctuation” pattern, mostly in CD4 T cells, involving mitochondrial energy production. Many of these genes mapped to one region of chromosome 11, and men showed age-related loss of chemical tags called methylation on a gene there (SSH3) that women did not.
In women, one pattern stood out. Genes that arm CD8 T cells to kill, such as GNLY, GZMA, GZMB, and NKG7, kept rising throughout life. In men, those same genes leveled off after about age 60. In other words, an older woman’s killer T cells appear to stay switched on longer.
The authors call this a double-edged sword, and I think that is exactly right. Sustained CD8 T cell activity may help older women respond better to vaccines and clear infections, which could help explain why women outlive men. The cost may be chronic activation, more inflammaging, T cell exhaustion, and a higher risk of autoimmunity. The authors also cite a 2026 mouse study in Immunity showing that aged circulating CD8 T cells and their secreted factors drive cognitive decline. They suggest that gently modulating cytotoxic CD8 T cell activity may be especially relevant for women.
Women also showed a pattern in which some features rose and then fell late in life, mostly in CD4 T cells. One example: B cells in older women showed declining levels of the molecules they use to present threats to CD4 T cells (called MHC class II), which a 2026 Science Immunology study recently linked to CD4 T cell aging.
The Iron Connection
One of the most practical findings involves iron. In women only, two genes that build ferritin, the protein your body uses to store iron, rose late in life in several immune cell types, along with a broader iron accumulation signature and genes tied to cell death. The authors connect this to menopause. Once monthly blood loss stops, iron stores tend to rise, and they note that national survey (NHANES) data show serum ferritin rising in women around age 50. Excess iron can push cells toward senescence, a state in which cells stop dividing and start releasing inflammatory signals.
This is a good example of how a lab finding becomes a clinical question. Ferritin is a simple blood test, and I check it routinely in midlife and older women.
Separate Clocks for Women and Men
The team also built “biological age clocks” using deep learning, a type of artificial intelligence that learns patterns from data. Clocks built separately for women and men predicted age more accurately than a combined model, reaching correlations above 0.87 in the training cohorts and above 0.7 in outside healthy cohorts. When the researchers tested the male clock on women, or the female clock on men, accuracy dropped. That strongly suggests the sexes follow different immune aging programs.
The authors are clear about the limits. The study looked at different people at different ages rather than following the same people over time; it measured blood only, and these clocks are first-generation tools, not something you can order from your doctor today.
What This Means for You
I find it beautiful that men and women, made in the same image yet different by design, carry those differences all the way down to how their immune cells age. Caring for that design well is part of good stewardship of the body we have been given.
The practical takeaway is about timing. The researchers describe immune aging as moving through punctuated transitions that may represent windows for intervention. If you are approaching or in your 40s, this is a good decade to get a clear baseline on inflammation and metabolic health. If you are a woman in or past menopause, or anyone entering your 60s, it is time to look again, with special attention to ferritin and inflammatory markers. Sleep, regular movement, strength training, a whole-food diet, and avoiding smoking remain the best-supported ways to keep inflammation in check at any age.
Can Natural Compounds Help? Only the Strongest Evidence Makes This List
People often ask me about natural products for immune aging, and the honest answer has two parts. First, no supplement has been shown to change the immune aging waves described in this study, and none has been proven to slow immune aging in a way that adds healthy years. Second, a small number of nutrients now have what most supplements lack: randomized, placebo-controlled trials in adults, ideally older adults, with outcomes that bear directly on the aging immune system itself, such as fewer infections, less autoimmune disease, or restored T cell numbers and function. General anti-aging results, such as a slowed epigenetic clock or better muscle endurance, do not count here, however interesting they are. That is the bar I used. Two nutrients clear it. The popular ones that do not, including several you may have asked about, are listed afterward with the reason why.
Zinc
Zinc is the least glamorous item on this list and the one I would start with. Your thymus, where new T cells mature, depends on a zinc-containing hormone called thymulin, and both zinc intake and absorption tend to decline with age.
The key trial is Prasad and colleagues’ 2007 study in the American Journal of Clinical Nutrition. Fifty healthy adults aged 55-87 were randomized to 45 mg of elemental zinc (as zinc gluconate) or placebo daily for 12 months. The zinc group had significantly fewer infections over the year, produced less of the inflammatory signal TNF-alpha with their immune cells, and had lower blood markers of oxidative stress. A second, smaller trial by Barnett and colleagues in 2016 enrolled nursing home residents aged 65 and older with low serum zinc and gave them 30 mg of zinc daily or a 5 mg control for 3 months. Serum zinc rose about 16% in the zinc group, and both T cell numbers and their ability to multiply in response to a challenge improved, although residents who started substantially deficient did not reach normal levels in 3 months.
The connection to the new study is direct. The Singapore team found fewer naive T cells and more inflammatory signaling in both sexes with age, and zinc is the nutrient most tightly tied to keeping T cell production and T cell function intact. The benefit is clearest for people who are low, and that is not rare: the NIH Office of Dietary Supplements notes that older adults in particular may have marginal zinc intakes.
Food comes first. Oysters, beef, pumpkin seeds, and legumes are good sources. If you supplement, 15-30 mg of elemental zinc daily is a reasonable range for most older adults, and a serum zinc level can tell you whether you need it at all. The NIH Office of Dietary Supplements sets the tolerable upper limit for adults at 40 mg daily and notes that intakes of 50 mg or more for weeks can block copper absorption, leading to anemia and nerve problems. Zinc can also cause nausea on an empty stomach and interferes with the absorption of quinolone and tetracycline antibiotics if taken at the same time, so separate them by several hours.
Vitamin D
Vitamin D receptors sit on nearly every immune cell, and vitamin D helps keep T cell responses balanced rather than overheated. The strongest human evidence comes from the VITAL trial, the largest randomized test of vitamin D ever run. In a 2022 analysis in The BMJ, Hahn and colleagues followed 25,871 US adults (men aged 50 and older, women aged 55 and older) who were randomized to 2,000 IU of vitamin D3 daily or placebo for a median of 5.3 years. Vitamin D reduced confirmed new autoimmune disease, including rheumatoid arthritis, polymyalgia rheumatica, autoimmune thyroid disease, and psoriasis, by 22%. Given that women carry most of the autoimmune burden, and that this new study points to sustained immune activation in older women, I find that result especially relevant.
For infections, Jolliffe and colleagues pooled 43 randomized trials with more than 48,000 participants in a 2021 meta-analysis in The Lancet Diabetes & Endocrinology. Vitamin D produced a small overall reduction in acute respiratory infections, and the protection was concentrated in trials that used daily doses of 400-1,000 IU. Large weekly or monthly doses did not help. The honest summary is that vitamin D will not transform immune aging, but correcting a low level is a modest, inexpensive, and well-tested step.
I suggest checking a 25-hydroxyvitamin D level before and after supplementing. Most adults do well on 1,000-2,000 IU daily, taken with a meal that contains some fat. More is not better. Long-term intake above 4,000 IU daily without monitoring raises the risk of high blood calcium and kidney stones, especially if you also take calcium supplements.
A Word About Movement
You asked about compounds, but I would be doing you a disservice if I didn’t mention exercise, because nothing in a capsule comes close. In a 2018 Aging Cell study by Duggal and colleagues, 125 amateur cyclists aged 55-79 who had stayed active for most of their adult lives had more naive T cells and more fresh emigrants from the thymus than inactive peers, with thymic output matching that of young adults. They also had higher levels of the thymus-protecting signal IL-7 and lower levels of IL-6, the inflammatory signal that shrinks the thymus. That is the clearest demonstration we have that an aging immune system responds to how we live.
What Did Not Make the Cut
Several popular options have real scientific interest but not the human evidence to earn a recommendation for immune aging. I include them because you will see them marketed for exactly this purpose.
Urolithin A came closest. Your gut bacteria make it from pomegranates, walnuts, and berries, and it works by prompting cells to recycle worn-out mitochondria. In a 2025 trial in Nature Aging, Denk and colleagues gave 50 healthy middle-aged adults 1,000 mg of urolithin A or placebo daily for 4 weeks and found more naive-like, less exhausted CD8 T cells, better fat-burning capacity in those cells, more NK cells, and lower inflammatory cytokines. That is the most immunosenescence-specific result of any compound on this page, and it touches two threads in the Singapore study: the loss of naive CD8 T cells and the mitochondrial changes seen in T cells. But it is a single 4-week study of 50 people, the product’s manufacturer was involved, and no one has shown fewer infections, better vaccine responses, or any other clinical immune outcome. I am watching it closely, and I would not call it proven.
Omega-3 fatty acids are a natural fit for inflammaging in theory, since EPA and DHA are building blocks for the molecules that switch inflammation off. Their only immune-specific test in a large trial, the omega-3 arm of VITAL, lowered new autoimmune disease by 15%, a result that did not reach statistical significance on its own. Omega-3s have other randomized evidence, including a small slowing of epigenetic age clocks in older adults, but that is general aging rather than immune aging, so it does not earn a place here. If you take fish oil for other reasons, keep two cautions in mind: it can add to bleeding risk with blood thinners, and a 2021 meta-analysis by Gencer and colleagues in Circulation found a higher risk of atrial fibrillation, especially above 1 g daily.
Reishi mushroom has one randomized trial with immune endpoints. Chen and colleagues reported in 2023 that 200 mg of a purified reishi beta-glucan daily for 12 weeks raised NK cell counts, NK cell killing activity, and the CD4/CD8 ratio in 157 healthy adults aged 18-55. That is encouraging, but it is a single industry-sponsored trial in younger adults with no infection outcomes, and it includes no older adults, where immunosenescence actually lives. Reishi can also affect platelets and has been linked to rare liver injury, so it is not something I recommend casually.
Pu-erh tea has no human trials on immune aging at all. Its only link to this research is indirect: tea polyphenols bind non-heme iron in the gut, and Hurrell, Reddy, and Cook showed in a classic human study that polyphenol-rich beverages taken with a meal cut iron absorption by 50-90%. For a postmenopausal woman watching her ferritin climb, tea with meals is a sensible, food-first habit, but that is an iron story rather than an immune one; pu-erh itself has never been tested for it, and if you are iron deficient, drink tea between meals instead.
Cistanche tubulosa is a desert plant valued in traditional Chinese medicine as a longevity tonic, and its phenylethanoid glycosides are anti-inflammatory and immune-modulating in cell and animal studies. No human trial has measured its effect on immune aging, and long-term safety data are limited. There is essentially no human evidence that cistanche supports an aging immune system.
Fisetin is a promising senolytic in mice, but the Mayo Clinic’s human trials have not reported results, so its effect on senescent immune cells in people is unknown. Quercetin has been studied in humans mainly in small pilot studies alongside the cancer drug dasatinib, not alone. NMN and other NAD+ boosters raise NAD+ levels in blood, but there are no meaningful human data on immune aging outcomes. Spermidine, found in wheat germ, natto, aged cheese, and mushrooms, has a small 2026 pilot study in adults over 65 reporting encouraging signals on immune cell senescence and vaccine response, but the findings were exploratory and need a full trial before they mean anything. TA-65, a telomerase activator derived from astragalus, has small, company-funded studies reporting fewer senescent CD8 T cells, which is not enough to build on. Probiotics have raised NK cell activity in some small trials in older adults, but results vary too widely between strains to rely on, and curcumin has no human data on immune aging at all.
My Bottom Line
If you want to support your immune system as you age, start with the foundations of sleep, movement, strength training, and a whole-food diet, then make sure you are not deficient in the two nutrients your immune cells most clearly depend on. Zinc has the most practical evidence: it reduced infections over a full year in older adults and restored T cell numbers and function in people who were low. Vitamin D reduced new autoimmune disease by 22% in the largest trial ever run, which matters given the sustained immune activation this study found in older women, and it modestly reduces respiratory infections at ordinary daily doses. Everything else, including omega-3s, urolithin A, reishi, pu-erh tea, and cistanche, is either an immune result that fell short of significance, a promising finding that no one has repeated, or simply untested for this purpose, and I would rather tell you that plainly than sell you a bottle.
A Note From Dr. Thomas
Supplements are not a substitute for medical care. Please talk with your physician before starting any of these, especially if you take blood thinners or antiplatelet medications, have liver or kidney disease, or are undergoing cancer treatment, since immune-active products can interact with chemotherapy and immunotherapy. Keep zinc at or below 40 mg daily unless your doctor is monitoring your copper, and do not take high-dose vitamin D without checking your blood level.
The best way to know where you stand is to measure. Comprehensive metabolic bloodwork that includes ferritin, 25-hydroxyvitamin D, serum zinc, and inflammatory markers such as hs-CRP gives you and your doctor a real starting point, and repeating it in your 40s and again in your 60s lines up beautifully with what this research shows. Our bodies are wonderfully made, and paying attention to them at the right moments is one of the most faithful things we can do.
References
- Barnett JB, Dao MC, Hamer DH, Kandel R, Brandeis G, Wu D, et al. Effect of zinc supplementation on serum zinc concentration and T cell proliferation in nursing home elderly: a randomized, double-blind, placebo-controlled trial. Am J Clin Nutr. 2016;103(3):942-951.
- Chen SN, Nan FH, Liu MW, Yang MF, Chang YC, Chen S. Evaluation of immune modulation by β-1,3; 1,6 D-glucan derived from Ganoderma lucidum in healthy adult volunteers, a randomized controlled trial. Foods. 2023;12(3):659.
- Denk D, Singh A, Kasler HG, D’Amico D, Rey J, Alcober-Boquet L, et al. Effect of the mitophagy inducer urolithin A on age-related immune decline: a randomized, placebo-controlled trial. Nat Aging. 2025;5(11):2309-2322.
- Duggal NA, Pollock RD, Lazarus NR, Harridge S, Lord JM. Major features of immunesenescence, including reduced thymic output, are ameliorated by high levels of physical activity in adulthood. Aging Cell. 2018;17(2):e12750.
- Franceschi C, Garagnani P, Parini P, Giuliani C, Santoro A. Inflammaging: a new immune-metabolic viewpoint for age-related diseases. Nat Rev Endocrinol. 2018;14(10):576-590.
- Gencer B, Djousse L, Al-Ramady OT, Cook NR, Manson JE, Albert CM. Effect of long-term marine omega-3 fatty acids supplementation on the risk of atrial fibrillation in randomized controlled trials of cardiovascular outcomes: a systematic review and meta-analysis. Circulation. 2021;144(25):1981-1990.
- Hahn J, Cook NR, Alexander EK, Friedman S, Walter J, Bubes V, et al. Vitamin D and marine omega 3 fatty acid supplementation and incident autoimmune disease: VITAL randomized controlled trial. BMJ. 2022;376:e066452.
- Hurrell RF, Reddy M, Cook JD. Inhibition of non-haem iron absorption in man by polyphenolic-containing beverages. Br J Nutr. 1999;81(4):289-295.
- Jolliffe DA, Camargo CA Jr, Sluyter JD, Aglipay M, Aloia JF, Ganmaa D, et al. Vitamin D supplementation to prevent acute respiratory infections: a systematic review and meta-analysis of aggregate data from randomised controlled trials. Lancet Diabetes Endocrinol. 2021;9(5):276-292.
- Klein SL, Flanagan KL. Sex differences in immune responses. Nat Rev Immunol. 2016;16(10):626-638.
- Márquez EJ, Chung CH, Marches R, Rossi RJ, Nehar-Belaid D, Eroglu A, et al. Sexual-dimorphism in human immune system aging. Nat Commun. 2020;11(1):751.
- Park H, Le Bert N, Bertoletti A, Tolwinski N, Gruber J, Behmoaras J. Sex-specific trajectories of nonlinear immune aging at single-cell level. Nat Commun. 2026;17:10008.
- Prasad AS, Beck FW, Bao B, Fitzgerald JT, Snell DC, Steinberg JD, et al. Zinc supplementation decreases incidence of infections in the elderly: effect of zinc on generation of cytokines and oxidative stress. Am J Clin Nutr. 2007;85(3):837-844.
