Aging and brain rejuvenation as systemic events

Abstract

The effects of aging were traditionally thought to be immutable, particularly evident in the loss of plasticity and cognitive abilities occurring in the aged central nervous system (CNS). However, it is becoming increasingly apparent that extrinsic systemic manipulations such as exercise, caloric restriction, and changing blood composition by heterochronic parabiosis or young plasma administration can partially counteract this age-related loss of plasticity in the aged brain. In this review, we discuss the process of aging and rejuvenation as systemic events. We summarize genetic studies that demonstrate a surprising level of malleability in organismal lifespan, and highlight the potential for systemic manipulations to functionally reverse the effects of aging in the CNS. Based on mounting evidence, we propose that rejuvenating effects of systemic manipulations are mediated, in part, by blood-borne 'pro-youthful' factors. Thus, systemic manipulations promoting a younger blood composition provide effective strategies to rejuvenate the aged brain. As a consequence, we can now consider reactivating latent plasticity dormant in the aged CNS as a means to rejuvenate regenerative, synaptic, and cognitive functions late in life, with potential implications even for extending lifespan. We review evidence of brain rejuvenation focusing on several systemic manipulations - exercise, caloric restriction, heterochronic parabiosis, and young plasma administration - and their ability to restore regenerative capacity, synaptic plasticity, and cognitive function in the brain.

Keywords: aging; cognition; heterochronic parabiosis; regeneration; rejuvenation.

Fig 1

Interplay between lifespan regulation and brain function. Schematic illustration depicts the unique duality of the brain to be both responsive to systemic lifespan regulation as well as serve as a central regulator of lifespan. Genetic studies have identified the FoxO family of transcription factors, Sirtuins and mTOR signaling pathway as molecular regulators that both promote longevity and mediate critical brain functions known to undergo age-related impairments such as learning and memory. Conversely, the brain has also been demonstrated to promote longevity through neuronal regulation, particularly via the hypothalamus region.

Fig 2

Currently known rejuvenating effects of systemic manipulations on the aged brain. Schematic illustration depicts individual systemic manipulations [exercise, caloric restriction (CR), heterochronic parabiosis, and young plasma administration] and their respective effect on each of the three main areas of rejuvenation (neurogenesis, synaptic plasticity, and cognitive function). Known enhancements are denoted by a red checkmark, contradictory reports are denoted as a red checkmark with a question mark, and unknown effects are denoted with a question mark.