Morphological and Metabolic Features of Brain Aging in Rodents, Ruminants, Carnivores, and Non-Human Primates

Brain aging in mammals is characterized by morphological and functional changes in
neural cells. Macroscopically, this process, leading to progressive cerebral volume loss and functional
decline, includes memory and motor neuron deficits, as well as behavioral disorders. Morphologically,
brain aging is associated with aged neurons and astrocytes, appearing enlarged and flattened, and
expressing enhanced pH-dependent β-galactosidase activity. Multiple mechanisms are considered
hallmarks of cellular senescence in vitro, including cell cycle arrest, increased lysosomal activity,
telomere shortening, oxidative stress, and DNA damage. The most common markers for senescence
identification were identified in (i) proteins implicated in cell cycle arrest, such as p16, p21, and
p53, (ii) increased lysosomal mass, and (iii) increased reactive oxygen species (ROS) and senescenceassociated secretory phenotype (SASP) expression. Finally, dysfunctional autophagy, a process
occurring during aging, contributes to altering brain homeostasis. The brains of mammals can be
studied at cellular and subcellular levels to elucidate the mechanisms on the basis of age-related
and degenerative disorders. The aim of this review is to summarize and update the most recent
knowledge about brain aging through a comparative approach, where similarities and differences in
some mammalian species are considered.