In a recent review published in Nature Neuroscience, researchers discussed cellular hallmarks of brain aging and therapeutic interventions to rejuvenate cognitive brain functions.
Aging induces cellular, functional, and molecular changes in the brain, leading to cognitive decay and increasing the susceptibility to neurodegenerative disease development. Lifestyle and systemic interventions could potentially reverse the effects of aging and restore cognitive function. However, it is unlikely that a single factor drives aging or that one therapeutic intervention would independently restore function to youthful levels.
Cognitive rejuvenation would probably require a combination of biomarker analyses to assess age-related changes and identify potential therapeutic targets to devise the best strategy, involving the administration of pro-youthful factors and inhibition of pro-aging factors, along with physical exercise and other lifestyle changes.
About the review
In the present review, researchers discussed age-associated changes in the brain and therapeutic approaches to reverse them.
Cellular hallmarks of aging
Concerning functional changes of neurons and circuits, aging leads to reduced hippocampal immediate early gene (IEG) expression [especially phosphorylated cAMP response element-binding protein (pCREB)], reduced expression of synaptic proteins and/or reduction in synaptic density, altered excitatory and/or inhibitory neuron inputs and neuronal excitability, and maladaptive neuronal network changes.
Concerning regenerative changes relating to adult neuronal stem cells (NSCs), subventricular zone (SVZ) neurogenesis, oligodendrocyte progenitor cells (OPCs), and myelin renewal with advancing age, a decrease in NPC proliferation and differentiation, and newborn neuron expression is observed. In addition, aging leads to lowered OPC proliferation, oligodendrocyte differentiation, and myelination.
Concerning inflammatory changes associated with microglia and astrocytes, with an increase in age, a concomitant increase in microglial reactivity, reactive oxygen species (ROS) generation, complement production, and increased impairments in phagocytosis and synaptic pruning are observed. In addition, astrocytes get reactivated with maladaptive synaptic homeostasis or pruning.
Concerning vasculature changes relating to the blood-brain barrier (BBB), advanced age is associated with an increase in vascular stiffness, vascular leakage, brain endothelial cell (BEC) inflammation, and BEC transcytosis mechanisms (increased caveolar and decreased receptor-mediated transport) are observed. With age, the pericyte coverage and cerebral blood flow (CBF) are reduced.
Pro-aging blood factors and immune cells include chemokine C–C motif ligand (CCL)-2 and 11, β2-microglobulin (B2M), tumor growth factor-β1 (TGF-β1), vascular cell adhesion molecule 1 (VCAM1), acid sphingomyelinase (ASM), cyclophilin A (CyPA), cluster of differentiation 8+ (CD8+) T lymphocytes, natural killer (NK) cells, and peripheral myeloid cells. CCL11, CCL2, and CD8+ T lymphocytes act primarily in the brain NSCs and microglial cells, whereas VCAM1, ASM, and CyPA target cranial vasculature cells. B2M and NK cells exclusively act on NSCs.
Therapeutic or rejuvenating interventions
Therapeutic interventions for cognitive rejuvenation are broadly classified as blood-based and lifestyle interventions. Blood-based interventions to restore cognitive function include heterochronic parabiosis, aged plasma administration, neutral blood exchange, and young bone marrow transplantation. Lifestyle interventions include exercise and caloric restrictions.
Pro-youthful blood factors can be administered to reverse the effects of aging. The factors include growth differentiation factor 11 (GDF11), osteocalcin (OCN), tissue inhibitor of metalloproteinases 2 (TIMP2), colony-stimulating factor 2 (CSF2), thrombospondin 4 (THBS4), SPARC-like protein 1 (SPARCL1), α-klotho and gonadotropin-releasing hormone (GnRH).
Other factors reported to enhance cognitive function include insulin-like growth factor 1 (IGF1), glycosylphosphatidylinositol (GPI)-specific phospholipase (GPI-PLD), selenoprotein P (SEPP1), clusterin or apolipoprotein J (ApoJ), irisin or fibronectin type III domain-containing protein (FNDC5), vascular endothelial growth factor (VEGF), lactate, platelet factor 4 (PF4), cysteine protease cathepsin B (CTSB), and ketone bodies (particularly β-hydroxybutyrate). GDF11, SEPP1, VEGF, clusterin, and lactate act at the blood vasculature level, whereas osteocalcin, TIMP2, CSF2, GnRH, IFG1, PF4, irisin, CTSB act at the cranial level. Ketone bodies may act at either level.
Pro-aging factors drive maladaptive neuroinflammatory changes, inhibit neurogenesis, inhibit TGF-β1, reduce spine density, increase microglial activation, increase vascular inflammation, and impair synaptic plasticity in the brain. On the other hand, anti-aging factors such as CSF2, TIMP2, α-klotho, SPARCL1, THBS4, and OCN (osteocalcin) restore synaptic and/or regenerative functions directly in the aged adult brain. α-klotho and GDF11 and act indirectly by improving vascular functions. SPARCL1 and THBS4 have improved neural cell functions in vitro; however, the in vivo effects are yet to be determined.
Exerkines or factors induced by physical exercise are mainly derived from musculature (referred to as myokines such as irisin and FNDC5) or the liver (referred to as hepatokines such as GPLD1, IGF1, clusterin, and SEPP1) and improve regenerative and synaptic functions of the brain. Taken together, the activation of pro-youthful factors and inhibition of factors that induce aging enhance synaptic plasticity and neurogenesis and lead to vascular remodeling and reduction in age-associated neuroinflammation.
To conclude, based on the review findings, with advancing age, the adult brain undergoes several changes at the molecular level that lead to cognitive decline among individuals. The identification of such changes could aid in the development of strategies targeted at inhibiting factors that promote aging and activating anti-aging factors, in conjunction with lifestyle interventions, to restore the youthfulness of the adult brain.