Journal
MECHANISMS OF AGEING AND DEVELOPMENT
Volume 197, Issue -, Pages -Publisher
ELSEVIER IRELAND LTD
DOI: 10.1016/j.mad.2021.111512
Keywords
Aging; Stress; Infection; Cognitive decline; Neuroimmune system; Microglia; Inflammation
Categories
Funding
- European Regional Development Fund (ERDF), through the Centro 2020 Regional Operational Programme [CENTRO-01-0145-FEDER-000008]
- COMPETE 2020-Operational Programme for Competitiveness and Internationalisation
- Portuguese national funds via FCT - Fundacao para a Ciencia e a Tecnologia [POCI-01-0145-FEDER-007440, UIBD/04539/2020, PTDC/NEUSCC/3247/2014, PTDC/MED-NEU/5993/2020]
- BIAL Foundation [264/2016]
- Programa Operacional Potencial Humano (POPH) [SFRH/BPD/120611/2016, SFRH/BD/144224/2019, SFRH/BD/144875/2019]
- Fundação para a Ciência e a Tecnologia [SFRH/BD/144224/2019, SFRH/BD/144875/2019, PTDC/MED-NEU/5993/2020] Funding Source: FCT
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The brain is highly susceptible to aging effects, particularly in relation to microglia dysfunction. Microglia acquire an age-related immunosenescent phenotype, leading to compromised immune responses and synaptic activity, contributing to cognitive decline and neurodegeneration associated with aging. Lifestyle and environmental factors play a role in driving microglia dysfunction at molecular and functional levels, suggesting potential interventions for reversing aging-related damage to the nervous system and immune system.
Among all major organs, the brain is one of the most susceptible to the inexorable effects of aging. Throughout the last decades, several studies in human cohorts and animal models have revealed a plethora of age-related changes in the brain, including reduced neurogenesis, oxidative damage, mitochondrial dysfunction and cell senescence. As the main immune effectors and first responders of the nervous tissue, microglia are at the center of these events. These cells experience irrevocable changes as a result from cumulative exposure to environmental triggers, such as stress, infection and metabolic dysregulation. The age-related immunosenescent phenotype acquired by microglia is characterized by profound modifications in their transcriptomic profile, secretome, morphology and phagocytic activity, which compromise both their housekeeping and defensive functions. As a result, aged microglia are no longer capable of establishing effective immune responses and sustaining normal synaptic activity, directly contributing to age-associated cognitive decline and neurodegeneration. This review discusses how lifestyle and environmental factors drive microglia dysfunction at the molecular and functional level, also highlighting possible interventions to reverse aging-associated damage to the nervous and immune systems.
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