Twelve Hallmarks of Aging
- Loss of proteostasis—the ability to maintain a functional protein pool
- Epigenetic alterations
- Telomere attrition
- Genomic instability
- Altered intercellular communication
- Stem cell exhaustion
- Cellular senescence
- Mitochondrial dysfunction
- Dysregulated nutrient sensing
- Chronic inflammation—persistent low-grade inflammation that increases with age
- Dysbiosis—microbiome imbalance affecting immunity, metabolism, and barrier integrity
- Impaired macroautophagy—the clearance of damaged cells and cellular components
Cellular Senescence
One of the primary hallmarks of aging is cellular senescence, where cells lose the ability to divide in response to acute or chronic damage. All cell types are susceptible to senescence, including slowly renewing tissues such as the heart and brain.
Accumulation of senescent cells can disrupt tissue architecture, impair organ function, and promote age-related diseases. In mouse studies, removing senescent cells reduced aging-related disorders and extended lifespan.
Senescence is triggered by telomere shortening and impaired nutrient supply, mitochondrial dysfunction, defective autophagy, and gene activity changes. Senescent cells secrete a specific set of pro-inflammatory molecules, forming the senescence-associated secretory phenotype (SASP), which alters the local environment, modulates immunity, and influences neighboring cell behavior.
Interferons as Potential Mediators of Cellular Senescence
Recent research has increasingly focused on type I and II interferons (IFNs) in the context of aging. IFNs are signaling proteins that coordinate various biological processes. There are three major types:
- Type I IFNs (e.g., IFN-α, IFN-β) act via the IFNAR receptor
- Type II IFN (IFN-γ) signals through the IFNGR receptor
- Type III IFNs (IFN-λ) bind to IL-10R2 and IFNLR1 receptors
ISG (interferon-stimulated gene) activity rises in aged tissues and senescent epithelial cells, suggesting IFNs could be a therapeutic target for anti-aging interventions.
Interferon and Cellular Senescence in Alzheimer’s Disease
Alzheimer’s disease (AD) is the most common form of dementia, mainly affecting older adults, with symptoms including memory loss, language impairment, and behavioral decline.
IFN-I signaling is pathologically activated in AD:
- Amyloid-beta (Aβ) plaques stimulate IFN-I production, modulating pro-inflammatory cytokine release and innate immune activity in the CNS
- Aβ-dependent overactivation of IFN-I in microglia worsens memory and inflammation. Blocking IFNAR improves memory, reduces microglial proliferation, and protects synapses
- Similar effects are observed in postmortem human brains: elevated IFN-I levels and ISG expression correlate with disease severity and complement activation
- Tau pathology in AD leads to a senescent-like microglial phenotype with increased IFN-I signaling
- Knocking down IFNAR in tauopathy mouse models restores microglial function and prevents senescence
IFN-γ (type II) also contributes to neurodegeneration during aging:
- Elevated IFN-γ in the elderly drives chronic neuroinflammation
- IFN-γ promotes microglial proliferation and affects synaptic signaling
- Microglia exacerbate AD by iron accumulation and reduced autophagy
- IFN-γ triggers microglial neurotoxic activation, contributing to oxidative stress, network dysfunction, and neuronal death
- Activated microglia increase Aβ production, trigger inflammatory proteins, and remodel synapses—leading to cognitive decline
- Brain atrophy in AD mouse models correlates with tau accumulation and T cell infiltration; IFN-γ inhibition reduces atrophy
Interferon and Cellular Senescence in Pulmonary Fibrosis
Pulmonary fibrosis is a progressive condition marked by alveolar damage, chronic inflammation, fibroblast proliferation, and extracellular matrix accumulation. It impairs breathing and is closely linked to aging.
Lung regenerative capacity declines with age, tipping the balance toward injury rather than repair.
IFNs are involved in fibrotic immune regulation:
- In idiopathic pulmonary fibrosis (IPF), IFN-γ signaling is active in macrophages, cytotoxic T cells, and NK cells
- Type I IFN activation is more prominent in interstitial lung diseases
- IPF patients show elevated IL-2, IL-1β, CCL3, CCL5, IFN-γ, and increased CD64 expression in monocytes, along with enhanced IFN-I response
- During IPF exacerbation, serum cytokine and chemokine levels from macrophages rise significantly, possibly due to elevated serum IFN-γ
Post-COVID pulmonary fibrosis may result from intense inflammation and cellular damage. In COVID-19 patients, IFN-related gene expression in T cells, NK cells, and monocytes is reduced. Suppressing IFN proteins and pathways may be key to fibrosis control.
IFN-γ demonstrates antifibrotic properties: it inhibits fibroblast activation, balances Th1/Th2 responses, and improves prognosis and survival in IPF.
Interferon and Skin Aging
Skin aging impairs protective and regulatory functions and is classified into intrinsic aging—natural chronological decline—and extrinsic aging driven by environmental factors such as UV radiation, ionizing radiation, and smoking. Interferons play a key role in these processes:
- IFN-β exposure increases reactive oxygen species in fibroblasts, activating DNA damage pathways and inducing senescence. Short-term IFN-β exposure reversibly halts the cell cycle, while prolonged exposure triggers p53-dependent senescence through DNA damage signaling.
- In keratinocytes, DNA damage activates innate immunity via the cGAS-STING pathway, stimulating IFN-β Inhibition of STING reduces IFN-β expression.
- IFN-α exhibits anti-angiogenic effects, reducing the number of skin microvascular endothelial cells and promoting SASP formation.
- IFN-α may also decrease dendritic cell populations in aging skin.
- IFN-γ contributes to aging through mitochondrial stress: mitochondrial damage leads to DNA release into the cytoplasm, triggering SASP. Preventing mitochondrial membrane permeability reduces mitochondrial DNA release and IFN-γ
Molecular Mechanisms: How Interferons Drive Cellular Aging
Interferons promote apoptosis and cellular senescence by activating DNA damage pathways and p53 and RB proteins. In aging fibroblasts, IFN-β expression increases, upregulating ISGs and suppressing cell growth. IFN-β reversibly halts the cell cycle and triggers p53-dependent senescence, while p53 inhibition can mitigate IFN-driven aging.
DNA-damaged cells produce IFN-β, exacerbating senescence and reducing stem cell function in response to telomere shortening.
During aging, retrotransposons such as LINE-1 and endogenous retroviruses like HERVK activate, stimulating the cGAS-STING pathway, amplifying SASP, and increasing IFN-I expression, accelerating cellular aging. Endogenous retroviral particles from senescent cells may spread aging signals across cells and tissues.
Modulating interferon pathways may slow cellular aging and promote healthy longevity.
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Research progress on interferon and cellular senescence
