Ageing, neurodegeneration and brain rejuvenation

   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.

   According to a 2015 United Nations report on world population ageing¹, the number of people aged 60 and older worldwide is projected to more than double in the next 35 years, reaching almost 2.1 billion people. Most of this growth will come from developing regions of the world, although the oldest old, who are more than 80 years of age, are the fastest growing segment of the population in developed regions. Despite these improvements in life expectancy, Alzheimer’s disease (AD) and related neurodegenerative conditions have arguably become the most dreaded maladies of older people. The observation that almost all aged brains show characteristic changes that are linked to neurodegeneration raises the question of whether these hallmarks represent lesser aspects of brain ageing that do not considerably affect function or whether they are the harbingers of neurodegenerative diseases (Figure 1). Immune cells and secreted communication factors, which are responsible for tissue homeostasis in general, probably play important parts in brain ageing and neurodegeneration. However, comprehending or controlling the immune response in ageing has been a challenge. In the ageing organism, the brain seems to be susceptible to both cell-intrinsic and local signals, as well as to cues from the systemic environment. Animal models suggest that cues that are present in the circulatory system can either accelerate or slow aspects of brain ageing and cognitive function. This Review will synthesize present knowledge on brain ageing and neurodegeneration and discuss the prospect of stalling or even reversing these processes through circulatory factors.

Figure 1Ageing, 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.