Age-associated Cognitive Decline: Insights into Molecular Switches and Recovery Avenues

Abstract

Age-associated cognitive decline is an inevitable phenomenon that predisposes individuals for neurological and psychiatric disorders eventually affecting the quality of life. Scientists have endeavored to identify the key molecular switches that drive cognitive decline with advancing age. These newly identified molecules are then targeted as recovery of cognitive aging and related disorders. Cognitive decline during aging is multi-factorial and amongst several factors influencing this trajectory, gene expression changes are pivotal. Identifying these genes would elucidate the neurobiological underpinnings as well as offer clues that make certain individuals resilient to withstand the inevitable age-related deteriorations. Our laboratory has focused on this aspect and investigated a wide spectrum of genes involved in crucial brain functions that attribute to senescence induced cognitive deficits. We have recently identified master switches in the epigenome regulating gene expression alteration during brain aging. Interestingly, these factors when manipulated by chemical or genetic strategies successfully reverse the age-related cognitive impairments. In the present article, we review findings from our laboratory and others combined with supporting literary evidences on molecular switches of brain aging and their potential as recovery targets.

Network models predict that pyramidal neuron hyperexcitability and synapse loss in the dlPFC lead to age-related spatial working memory impairment in rhesus monkeys

“…First, we presented new empirical data from rhesus monkeys across the adult age span, consistent with past studies, showing that working memory impairment and increased FRs of neurons occur in some middle-aged monkeys. This replicated previous studies showing a decline in cognitive performance from young to aged monkeys (Herndon et al, 1997;Moore et al, 2003;Moore et al, 2006;Konar et al, 2016;Motley et al, 2018), and a concomitant increase in Rn and FR of dlPFC pyramidal neurons (Chang et al, 2005;Coskren et al, 2015). These data motivated the modeling, and were used to constrain a bump attractor network model of the DRT (Wimmer et al, 2014) and our network model of working memory retention in the DRSTsp.…”

Spontaneous oscillatory markers of cognitive status in two forms of dementia

“…Underpinnings of age‐related structural changes are typically associated with alterations in the synaptic properties of otherwise intact neurons and neuronal circuits; in contrast the predominant changes in pathological aging as in dementia are related to neuronal death (Fjell & Walhovd, ; Morrison & Hof, ). Evidence suggests that the inability to maintain high metabolic demands of large neurons, and profound alterations in synaptic plasticity and in gene expression mediate these changes over healthy aging (Fjell & Walhovd, ; Konar, Singh, & Thakur, ).…”

Role of green tea catechins in prevention of age‐related cognitive decline: Pharmacological targets and clinical perspective

“…In neural tissue, mTOR and its downstream signaling pathways are essential for maintaining neuronal recovery, memory retention, as well as synaptic plasticity (Tramutola, Lanzillotta, & Di Domenico, 2017). Proteases such as neuropsin that are present in the synaptic cleft and cleave cell adhesion molecules are capable of synaptic remodeling as well as synaptic connectivity and plasticity (Konar et al, 2016) (Eckert, 2010;Mathersul & Rosenbaum, 2016). Natural diets with significant preventative effects on cognitive decline include fruits and vegetables, natural antioxidant agents as well as natural omega-3 from nuts and flaxseed.…”