“Age slowly, live well”
When influenza, pneumonia, and other infections run rampant, we always pay extra attention to the elderly: they are more vulnerable to infection, develop more severe symptoms when ill, and even respond less effectively to vaccines than young people. Scientists refer to this age-related decline in immune function as immunosenescence.
Recently, researchers from West China Hospital of Sichuan University and Huazhong University of Science and Technology published a landmark review (IF=52.7) in Signal Transduction and Targeted Therapy, a sub-journal of Nature[1]. The review comprehensively summarizes age-related changes in the immune system at the molecular, cellular, and disease levels, and details existing intervention strategies.
This review not only uncovers the core drivers of immunosenescence but also provides scientific evidence for “delaying aging through immune regulation.” After all, a “young” immune army may be the best defense against the ravages of time.
01 Signaling Pathways: The Out-of-Control Switches of Immunosenescence
Immunosenescence hides many mysteries: Why do cells suddenly “run amok” and release large amounts of inflammatory factors? Why do autophagic cells (which clear cellular “trash”) stop working? Behind these abnormal behaviors lie distorted pathways or blocked signals.
NF-κB Signaling Pathway
The NF-κB pathway is normally activated briefly in response to cell damage. However, with aging, endogenous DNA damage and oxidative stress accumulate, keeping this “switch” constantly triggered—triggering a chain reaction:
- Inducing chronic inflammation and impairing immune surveillance;
- Upregulating anti-apoptotic proteins, allowing senescent immune cells to persist (increasing cancer risk);
- Worse still, NF-κB disrupts other pathways: it activates the mTOR pathway and inhibits autophagy. Defective autophagy leads to the accumulation of old proteins and mitochondria, exacerbating oxidative stress.
This creates a terrifying vicious cycle: Damage → NF-κB activation → More damage → Constant activation → Even more damage…
mTOR Signaling Pathway
The mTOR pathway consists of two complexes: mTORC1 and mTORC2.
- mTORC1 activity shows a widespread, harmful overactivation trend with aging. It is a key driver of autophagy inhibition, protein homeostasis imbalance, and cellular senescence—suppressing mTORC1 has long been a major anti-aging strategy.
- In contrast, mTORC2’s changes and effects are more complex: excessive activation impairs T cell receptor (TCR) responsiveness and proliferation, yet it is critical for maintaining specific immune memory. Thus, the mTOR pathway requires more than a “one-size-fits-all” approach; mTORC2 function should be supported in a tissue-specific manner.
JAK-STAT Signaling Pathway
The JAK-STAT pathway is also prone to dysregulation with aging:
- Overactivation of STAT3 continuously drives the massive release of pro-inflammatory factors (e.g., IL-6, IL-23), forming persistent senescence-associated secretory phenotype (SASP) and chronic inflammatory signals.
- Activation of JAK1/2 amplifies this inflammatory state, accelerating immune aging.
- Overactivated STAT3 also disrupts immune balance; mutations in JAK3 and STAT5B impair the immune tolerance of regulatory T cells (which prevent the immune system from attacking its own tissues), triggering autoimmune diseases.
- It even interferes with hematopoietic stem cell (HSC) differentiation, skewing HSCs toward myeloid cells rather than lymphocytes.
cGAS-STING Signaling Pathway
TIMEPIE has previously covered the cGAS-STING pathway in detail Briefly:
DNA leaked into the cytoplasm (due to DNA damage, mitochondrial dysfunction, etc.) continuously activates this key DNA-sensing pathway, exacerbating age-related chronic inflammation. It also impairs the secretion of type I interferons (IFN-I), which undermines the ability to transmit antigen information to T cells.
DNA leaked into the cytoplasm (due to DNA damage, mitochondrial dysfunction, etc.) continuously activates this key DNA-sensing pathway, exacerbating age-related chronic inflammation. It also impairs the secretion of type I interferons (IFN-I), which undermines the ability to transmit antigen information to T cells.
Downregulated Signaling Pathways
- AMPK Pathway: As a central energy sensor, AMPK normally promotes autophagy by inhibiting mTOR and activating ULK1, controls inflammation by suppressing NF-κB, and enhances mitochondrial function via the PGC-1α/SIRT1 pathway. However, loss of AMPKα1 in aged CD8+ T cells impairs memory T cell formation under metabolic stress.
- Melatonin Pathway: Melatonin secretion by the pineal gland decreases with age, losing its multi-faceted protective effects: it once directly scavenged free radicals, upregulated antioxidant enzymes (e.g., superoxide dismutase), and optimized mitochondrial function and autophagy via the SIRT1 pathway.
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Sirtuin Pathway: The sirtuin protein family is a classic group of “longevity proteins” that rely on NAD+ for deacetylation:
- SIRT1 inhibits the transcriptional activity of NF-κB;
- SIRT3 delays stem cell senescence by maintaining mitochondrial integrity;
- SIRT6 regulates class switch recombination in B cells.
Regrettably, sirtuin activity generally declines with age—especially reduced SIRT1 and SIRT3, which are associated with many age-related symptoms.
02 Cellular Mechanisms: Systemic Collapse of the Immune Army
Abnormal signaling pathways cause immune cell dysfunction—a systemic collapse affecting hematopoietic stem cells to all types of immune cells.
Hematopoietic Stem Cells (HSCs)
With aging, HSC numbers seem to increase, but their function declines:
- Reduced autophagy leads to the accumulation of damaged DNA and mitochondria;
- Aged HSCs preferentially differentiate into myeloid cells rather than lymphocytes, resulting in a severe shortage of adaptive immune “troops.”
Myeloid Lineage Cells
Myeloid cells include various innate immune cells (neutrophils, macrophages, monocytes):
- Neutrophils: Normally short-lived, but with aging, they become “holdouts”—even changing their behavior to release more inflammatory factors and neutrophil extracellular traps (NETs).
- Monocytes: Continuously produce pro-inflammatory factors (e.g., IL-6, TNF-α) with aging.
- Macrophages: Show reduced phagocytic function.
These cells spread inflammation throughout the body, accelerating tissue aging and damage.
Lymphoid Lineage Cells
Lymphoid cells include some innate immune cells (e.g., NK cells) and adaptive immune cells (T cells, B cells):
Thymic Involution: A Hallmark of Immunosenescence
Thymic shrinkage drastically reduces the production of “new recruit” T cells. This not only causes a shortage of new troops but also decreases the diversity of naive T cells—leaving the immune army unable to recognize and respond to emerging pathogens. Aged T cells also struggle to function in the “battlefield” of old age.
T cell senescence is irreversible: senescent T cells show cell cycle arrest and reduced proliferation. Critical CD8+ T cells, in particular, suffer from mitochondrial dysfunction (energy shortage), further weakening their performance. B cells also function poorly with aging.
Memory T and B cells (the “veterans”) can partially compensate for the lack of new recruits by quickly responding to previously encountered pathogens—but this comes at the cost of reduced new troop replenishment and overall response quality. This explains why the elderly often have poor vaccine responses.
Dendritic Cells (DCs)
DCs play a key role in capturing antigens and activating adaptive immunity. With aging:
- DCs show reduced antigen phagocytosis and migration;
- They release fewer pro-inflammatory factors in response to lipopolysaccharide (LPS, a foreign threat to the immune system);
- Their ability to activate CD4+ T cells weakens;
- Aged DCs also exacerbate chronic respiratory inflammation and promote inflammatory T cell differentiation in autoimmune diseases.
03 The Disease Vortex: The Butterfly Effect of Aged Immunity
Neurodegenerative Diseases
With aging, the nervous and immune systems develop an interdependent relationship. Peripheral immunosenescence and inflammation trigger neuroinflammation (persistent low-grade inflammation in the central nervous system), marked by elevated C-reactive protein, IL-6, and TNF-α. This accelerates brain cell senescence and is closely linked to neurodegenerative diseases such as Alzheimer’s disease (AD) and Parkinson’s disease (PD).
Alzheimer’s Disease (AD)
AD is hard to detect in early stages; cognitive and memory impairments only appear in later stages and worsen over time. Abnormal amyloid-β (Aβ) aggregation occurs, but aged microglia (the brain’s resident macrophages) lose their ability to clear Aβ—instead releasing more inflammatory factors. Excessive Aβ deposits continuously activate microglia and astrocytes, triggering persistent hyperinflammation, mitochondrial dysfunction, neuronal damage, and cell death—leading to cognitive decline and memory loss.
Parkinson’s Disease (PD)
PD patients face a different challenge: misfolded α-synuclein forms Lewy bodies in the brain, causing dopamine neuron death. Immune cells that should protect neurons instead do harm: senescent CD4+ T cells in peripheral blood cross the blood-brain barrier, accelerating neuronal damage.
Cancer
Increased cancer risk is also linked to immunosenescence:
- Senescent immune cells secrete SASP factors, which directly stimulate cancer cell growth, promote angiogenesis, assist cancer metastasis, and create a favorable microenvironment for tumors.
- Oxidative stress hinders tumor detection and specific T cell activation, promoting immune suppression.
Immunosenescence also impairs cancer immunotherapies: conventional tumor therapies often rely on T cell-mediated approaches, but T cells senesce. Senescent T cells recruit effector T cells and establish an immunosuppressive microenvironment. Multiple studies show that immune checkpoint inhibitors (e.g., PD-1 inhibitors) and cancer vaccines are often less effective in the elderly.
Other Diseases
Immunosenescence also triggers a range of seemingly unrelated diseases, including infectious diseases, autoimmune diseases, age-related macular degeneration, metabolic disorders, and cardiovascular diseases.
Though these diseases differ, their essence is similar: like an aging machine, immune cells either respond sluggishly (e.g., failing to clear infections) or overreact (e.g., attacking the body’s own tissues). Scientists are now exploring key targets in immunosenescence to find new solutions for these diseases.
04 Turning Back the Clock: Breaking the Deadlock with Targeted Therapies
Multi-level intervention strategies—from molecular pathway regulation and immune cell remodeling to nutritional and lifestyle adjustments—offer diverse solutions for immunosenescence.
Targeting Signaling Pathways
| Target | Intervention Strategy | Representative Drugs/Methods | Effects |
|---|---|---|---|
| NF-κB Pathway | Inhibition | 8K-NBD, bortezomib, fisetin, EF24 | Reduces oxidative stress and inflammation |
| mTOR Pathway | Inhibition | Rapamycin, PP242, Rapalink-1, RTB101/RAD001 | Extends lifespan, improves immune function, reduces infection risk |
| JAK-STAT Pathway | Inhibition | Ruxolitinib, NVP-BSK805 | Clears senescent cells, improves metabolism and muscle regeneration |
| AMPK Pathway | Activation | Metformin | Improves mitochondrial function |
| Melatonin Pathway | Supplementation | Melatonin | Protects the nervous system |
| Sirtuin Pathway | Activation | Resveratrol, NAD+ precursors | Delays stem cell senescence, improves metabolic diseases |
| PI3K/AKT Pathway | Blockade | Quercetin | Induces autophagy, improves tissue fibrosis |
| FOXO4-p53 Pathway | Blockade | FOXO4-DRI | Restores organ function |
Targeting Immune Cells
| Target | Intervention Strategy | Representative Drugs/Methods | Effects |
|---|---|---|---|
| Hematopoietic Stem Cells | Restore telomerase activity, inhibit ROS | CASIN, SIRT3 activators, AAV-TERT gene therapy | Improves hematopoietic function, reverses bone marrow senescence |
| T Cells | Cytokine therapy, thymic regeneration (KGF), sex hormone regulation | rhIL-7, palifermin, goserelin | Enhances T cell proliferation and diversity, improves vaccine response |
| B Cells | Inhibit TLR signaling, clear senescent B cells | Anti-CD20 antibodies, TLR7/9 inhibitors | Reduces autoantibody production, restores humoral immunity |
| NK Cells | Inhibit NKG2A receptor, supplement miR-181a-5p | Anti-NKG2A monoclonal antibodies | Enhances cytotoxicity, clears senescent cells |
| Macrophages/Monocytes | Inhibit p38-MAPK/COX-2, promote M2 polarization | Metformin, IL-4 | Reduces inflammation, improves phagocytic function |
Remodeling Immune Organs
| Organ | Intervention Strategy | Effects |
|---|---|---|
| Thymus | FOXN1 overexpression, young serum EVs, KGF/IL-22 cytokines | Promotes thymic epithelial cell (TEC) regeneration, increases naive T cell output |
| Bone Marrow | Young bone marrow transplantation, β3-adrenergic receptor agonists | Restores the hematopoietic microenvironment, improves HSC function |
| Lymph Nodes/Spleen | Synthetic lymphoid organ transplantation, anti-fibrotic therapy | Reconstructs lymphoid structure, enhances immune surveillance |
Nutritional and Lifestyle Interventions
| Category | Intervention | Effects |
|---|---|---|
| Diet | Omega-3, antioxidants (vitamin C), probiotics | Regulates gut microbiota, reduces inflammation |
| Exercise | Moderate aerobic exercise | Enhances T cell and NK cell function, reduces chronic inflammation |
| Stress Management | Meditation, yoga | Lowers cortisol, improves immune homeostasis |
Vaccination
Booster immunization (e.g., mRNA vaccines) compensates for age-related declines in antibody responses.
05 Future Outlook: The Next Frontier of Immunosenescence
As scientists deepen their understanding of immunosenescence mechanisms, we stand at the forefront of an exciting medical revolution. However, challenges remain: poor efficacy of single therapies, side effects of clinical applications, whether gene editing is a “Pandora’s box,” and balancing technology with nature, AI with data security. We must maintain a scientific and prudent attitude—future exploration will require both interdisciplinary collaboration and respect for the essence of life.
References
[1] FU Y, WANG B, ALU A, et al. Immunosenescence: signaling pathways, diseases and therapeutic targets [J]. Signal Transduction and Targeted Therapy, 2025, 10(1): 250.
[1] FU Y, WANG B, ALU A, et al. Immunosenescence: signaling pathways, diseases and therapeutic targets [J]. Signal Transduction and Targeted Therapy, 2025, 10(1): 250.