Ageing in the brain: mechanisms and rejuvenating strategies

Abstract

Ageing is characterized by the progressive loss of cellular homeostasis, leading to an overall decline of the organism's fitness. In the brain, ageing is highly associated with cognitive decline and neurodegenerative diseases. With the rise in life expectancy, characterizing the brain ageing process becomes fundamental for developing therapeutic interventions against the increased incidence of age-related neurodegenerative diseases and to aim for an increase in human life span and, more importantly, health span. In this review, we start by introducing the molecular/cellular hallmarks associated with brain ageing and their impact on brain cell populations. Subsequently, we assess emerging evidence on how systemic ageing translates into brain ageing. Finally, we revisit the mainstream and the novel rejuvenating strategies, discussing the most successful ones in delaying brain ageing and related diseases.

Keywords: Ageing; Brain; Cognition; Neurodegeneration; Rejuvenation.

Fig. 1

Hallmarks of brain ageing. Scheme depicting the hallmarks of ageing in the brain described in this review: genomic instability, telomere attrition, epigenetic alterations, loss of proteostasis, dysregulated metabolism (including nutrient sensing and mitochondrial dysfunction), cellular senescence, stem cell exhaustion, and altered intercellular communication. The pyramidal illustration represents the primary hallmarks (on the bottom), antagonistic (secondary) hallmarks emerging in response to the primary hallmarks, and the tertiary integrative hallmarks, ultimately leading to tissue homeostasis failures and dysfunction

Fig. 2

Impact of local and systemic ageing in brain health. Both neural cellular intrinsic factors and extrinsic systemic defects can contribute to the decline in brain function during ageing. Locally, brain cells can accumulate age-related damage, due to mitochondria dysfunction, oxidative stress, inflammation, or protein aggregation, which alters both neural cell survival but also core neural circuitry, and ultimately brain function. Systemic tissue ageing impacts brain health decline with age: periphery-derived factors such as inflammation mediators, SASP, peripheral immune invasion, and oxidative stress mediators that can reach the brain. ROS reactive oxygen species, SASP senescence-associated secretory phenotype, BBB blood–brain barrier

Fig. 3

Blood–brain barrier (BBB) dysfunction in ageing. The brain is protected from the periphery by the BBB, which maintains brain homeostasis by controlling the selective crossing of molecules. The BBB involves brain endothelial cells, mural cells (pericytes and vascular smooth muscle cells), astrocytes, neurons, microglia, and the basal lamina. BBB disruption in ageing is well documented, being a probable route for systemic factors, such as inflammatory mediators, cytokines, immune cells, and other molecules, to reach the brain and induce cellular and tissue dysfunction. ROS: reactive oxygen species; SASP: senescence associated secretory phenotype

Fig. 4

Rejuvenating strategies to improve brain health. Scheme illustrating systemic strategies found to be beneficial for brain health in ageing. With ageing comes damage accumulation in the organism, leading to increased organismal tissue dysfunction and inflammation. The brain is affected by the age-related accumulation of peripheral damage and also local damage, leading to morphological and functional alterations. Therapeutic interventions, such as heterochronic parabiosis, exercise, caloric restriction, counteracting senescence, cellular reprogramming and metabolic interventions, have a positive effect counteracting the damage accumulation that leads to brain ageing by acting systemic and/or locally in the brain