From necroptosis to neuroinflammation: Unraveling mechanisms and therapeutic targets in age-related cognitive decline

Apr 29, 2026Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie

From Cell Death to Brain Inflammation: Understanding Causes and Treatment Targets in Age-Related Thinking Decline

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Longevity & Aging on OpenScience ↗PubMed ↗DOI ↗

Abstract

Aging is associated with the upregulation of necroptosis-related proteins in neural tissues.

Immunosenescence leads to a decline in immune competence and chronic inflammation, termed inflammaging.
Chronic inflammation is linked to neuronal damage and neurodegenerative diseases such as Alzheimer's and Parkinson's.
Necroptosis may serve as a mediator between inflammation and neurodegeneration, contributing to neuronal loss.
Core molecular effectors of necroptosis, including RIPK1, RIPK3, and MLKL, are increasingly expressed in aged neural tissues.
Emerging biomarkers like phosphorylated MLKL and specific microRNAs may aid in early detection of neurodegenerative conditions.

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Aging is the major risk factor for several chronic conditions, including cognitive decline and dementia. It is accompanied by profound immune alterations characterized by a progressive decline in immune competence, a process known as immunosenescence. The resulting dysregulation of immune function leads to the overproduction of proinflammatory cytokines and fuels a persistent, low-grade inflammatory state termed inflammaging. This chronic inflammation contributes to dysfunction across the central and peripheral nervous systems, promoting neuronal damage and accelerating neurodegenerative processes such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and other age-related cognitive disorders. Within this framework, prolonged activation of inflammatory pathways can trigger regulated forms of cell death. Among these, necroptosis has recently emerged as a potential mediator linking inflammaging to neurodegeneration. Its core molecular effectors, including the receptor-interacting protein kinases RIPK1 and RIPK3 and the mixed-lineage kinase domain-like protein (MLKL), are increasingly expressed in aged neural tissues, promoting the release of damage-associated molecular patterns (DAMPs) that amplify glial activation, oxidative stress, and blood-brain barrier disruption. Growing evidence suggests that necroptotic signaling may be upregulated in the aging brain and in neurodegenerative disorders, where it could contribute to neuronal loss and cognitive impairment. This review discusses the potential role of necroptosis in the continuum between inflammation and neurodegeneration, highlighting emerging diagnostic and therapeutic perspectives. Epigenetic and circulating biomarkers, such as phosphorylated MLKL and specific microRNAs, may support early detection, while pharmacological and nutraceutical strategies targeting necroptosis show promising neuroprotective effects in preclinical studies.