Ageing, neurodegeneration and brain rejuvenation

Abstract

Although systemic diseases take the biggest toll on human health and well-being, increasingly, a failing brain is the arbiter of a death preceded by a gradual loss of the essence of being. Ageing, which is fundamental to neurodegeneration and dementia, affects every organ in the body and seems to be encoded partly in a blood-based signature. Indeed, factors in the circulation have been shown to modulate ageing and to rejuvenate numerous organs, including the brain. The discovery of such factors, the identification of their origins and a deeper understanding of their functions is ushering in a new era in ageing and dementia research.

Figure 1. Ageing, neurodegeneration and brain rejuvenation

As the brain ages, abnormal protein assemblies and inclusion bodies take hold and abnormal lysosomes are observed more frequently. It is unclear whether these defects promote ageing and neurodegeneration or whether they are innocent bystanders. Aged brains become highly prone to neurodegenerative diseases in which the same lesions amass as those that are found in old brains in smaller numbers. The relationship between such lesions and cognitive impairment is often blurred and normal aging and neurodegeneration and dementia can overlap. The concept of rejuvenation posits that old brains are malleable and that aspects of the ageing process can be reversed to a younger stage. If this can be achieved, it might also be possible to slow or reverse neurodegeneration and cognitive impairment.

Figure 2. Cell-specific and pathway-specific acceleration of ageing

Ageing can be dissected into individual processes, including a loss of protein homeostasis that leads to the development of aggregates and inclusion bodies, DNA damage, lysosomal dysfunction, epigenetic changes and immune dysregulation. The genetic predisposition of an individual, together with his or her exposure to the environment, determine the incidence and prevalence of the lesions that result from such processes, probably in a cell-specific manner. Various diseases might develop in accordance with the spatiotemporal distribution of the lesions.

Figure 3