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How autophagy changes with age

Autophagy is a lysosomal degradation pathway whose activity declines with age in many tissues. This page summarises research on the molecular mechanisms, model systems, and interventions studied in relation to age-relate

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How autophagy changes with age

Autophagy (from the Greek auto, self, and phagein, to eat) is a conserved lysosomal degradation pathway that removes damaged organelles, protein aggregates, and other cytoplasmic components. It is not a single molecule but a multi-step process executed by autophagy-related (ATG) proteins, including the initiation complex components ULK1 and ATG13. In aged organisms, autophagic flux is widely reported to decline, although the magnitude and tissue specificity vary. The pathway is regulated by nutrient-sensing kinases such as AMPK and mTOR, and its activity is influenced by energy availability.

Research on age-related autophagic changes centres on the ATG protein family and the lysosomal machinery, with crosstalk to DNA-damage and senescence pathways.

Research Studies

ATG13 and influenza A virus restriction in cell culture

ATG13 is a component of the autophagy initiation complex. In cell-based assays, ATG13 was found to restrict influenza A virus (IAV) replication while potentiating type I interferon signalling. Coimmunoprecipitation showed that ATG13 interacts with MAVS and recruits the E3 ubiquitin ligase ASB1 to catalyse K63-linked polyubiquitination at MAVS residue K348, amplifying the downstream antiviral cascade [2]. This work was performed in vitro and does not directly address ageing.

LSD1-mediated ATM demethylation in senescence and organ ageing

Lysine-specific demethylase 1 (LSD1) was upregulated in aged organs and senescent cells. In response to natural ageing or ionizing radiation, LSD1 interacted with and demethylated ATM at lysine 3,016, sustaining ATM phosphorylation and amplifying DNA damage signalling [3]. This mechanism links epigenetic regulation to cellular senescence and organ ageing in animal models.

Astrocytic autophagy impairment in Parkinson's disease models

In Parkinson's disease (PD), astrocyte dysfunction is increasingly viewed as an active driver of pathogenesis. Pathological α-synuclein triggers astrocytic failure, including impaired proteostasis via ubiquitin-proteasome and autophagy-lysosomal pathways, glymphatic collapse due to aquaporin-4 depolarisation, and neuroinflammation via microglial crosstalk and NLRP3 inflammasome activation [1]. These findings derive from cellular and animal models of PD.

Astaxanthin and granulosa-cell autophagy in a pilot randomised trial

A triple-blind, placebo-controlled pilot randomised trial enrolled 50 women with polyendocrine metabolic ovarian syndrome (PMOS)-related anovulatory infertility. Participants received astaxanthin (12 mg/day) or placebo, and the study evaluated whether astaxanthin modulates autophagy-related signalling in granulosa cells and how these molecular effects relate to ovarian response [6]. This is a human pilot study; results should be considered preliminary.

Fisetin and amyloid-beta-induced neurotoxicity in SH-SY5Y cells

In silico and in vitro studies using human neuroblastoma SH-SY5Y cells examined fisetin, a flavonoid, against amyloid-beta (Aβ1-42)-induced neurotoxicity. Fisetin was predicted to bind ULK1 (an autophagy marker), p21 (a senescence/cell-cycle marker), and synaptophysin (a synaptic marker) with high stability [7]. These are cell-based and computational findings, not human data.

Fasting, exercise, and diet in depression: an ongoing clinical study

A clinical study is investigating how lifestyle factors such as physical activity and diet-related processes may influence autophagy, a natural cellular process influenced by energy availability, in the context of depression [5]. This study is registered but results are not yet available.

Inorganic phosphate and muscle energetics in the context of ultra-processed foods

Chronic excess of inorganic phosphate (Pi) additives from ultra-processed foods has been proposed to impair skeletal muscle energetics and cardiorespiratory fitness [8]. While this work does not directly measure autophagy, it addresses a pathway that intersects with nutrient-sensing and cellular quality control.

Hypothalamic autophagy in POMC and AgRP neurons

In the arcuate nucleus, autophagy exerts divergent metabolic effects in the two principal appetite-regulating neuronal populations, POMC and AgRP neurons. This research area links hypothalamic nutrient sensing, leptin responsiveness, and intracellular quality control to obesity [9].

Hepassocin, AMPK, and liver ageing

Hepassocin (HPS), a hepatokine, has been reported to prevent age-related liver senescence and facilitate liver regeneration by activating AMPK [10]. This work was conducted in animal models.

Senescence and radiation-induced atrial fibrillation

Radiation-induced atrial fibrillation has been linked to cellular senescence via the GATA4–NF-κB pathway, and senolytic therapy with dasatinib and quercetin (D/Q) was found to rescue the phenotype in a model of radiation-induced heart disease [11]. This is an animal study.

Prevotella intermedia and alveolar macrophage function

Prevotella intermedia culture supernatant has been shown to impair alveolar macrophage function and promote Mycobacterium avium persistence in vitro [12]. This finding relates to host defence and autophagy-adjacent processes but is not directly about ageing.

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