Neurodegeneration

Neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis and frontotemporal lobar dementia are among the most pressing problems of developed societies with aging populations, with neurons being the main targets of disease. ^[1] Parkinson disease is the most common neurodegenerative movement disorder, characterized by loss of dopaminergic neurons in the substantia nigra and accumulation of misfolded alpha-synuclein in Lewy bodies. ^[2] Amyotrophic lateral sclerosis is an idiopathic, fatal neurodegenerative disease of the human motor system, and Huntington's disease is an autosomal-dominant progressive neurodegenerative disorder caused by an expanded CAG repeat in the huntingtin gene. ^{[3] [4]}

A common cellular mechanism across Alzheimer's, Parkinson's, Huntington's, ALS and prion diseases is protein aggregation into inclusion bodies consisting of misfolded protein in a beta-sheet conformation, termed amyloid. ^[5] Mitochondrial dysfunction and oxidative stress have a central role in ageing-related neurodegenerative diseases, occurring early and contributing causally to disease pathogenesis. ^[6] Neurodegeneration occurs in part because the neuronal environment is affected during disease through a cascade of processes collectively termed neuroinflammation, involving glial cells and the blood-brain barrier. ^[1] Ageing drives neurodegeneration through biological hallmarks including genomic instability, telomere attrition, epigenetic alterations, loss of proteostasis, mitochondrial dysfunction, cellular senescence, deregulated nutrient sensing, stem cell exhaustion and altered intercellular communication. ^[7] Senescent cells accumulate in the nervous system with ageing and neurodegenerative disease and may predispose a person to a neurodegenerative condition or aggravate its course.

Ageing is the primary risk factor for most neurodegenerative diseases, and one in ten individuals aged 65 years or older has Alzheimer disease, with prevalence continuing to increase with increasing age. ^[7] Alzheimer's disease is the leading cause of dementia, accounting for 50-70% of cases. ^[9] In Europe the estimated prevalence and incidence of Parkinson disease are approximately 108-257 per 100,000 and 11-19 per 100,000 per year respectively, with familial forms accounting for only 5% to 15% of cases. ^[2] In a systematic review the incidence of amyotrophic lateral sclerosis ranged from 0.26 per 100,000 person-years in Ecuador to 23.46 per 100,000 person-years in Japan, and point prevalence ranged from 1.57 to 11.80 per 100,000. ^[10] The diagnostic paradigm for Parkinson's disease is shifting toward a biological definition, similar to Alzheimer's disease and Huntington's disease, based on in vivo detection of neuronal alpha-synuclein aggregation, neurodegeneration and genetics. ^[11]

Few or no effective treatments are available for ageing-related neurodegenerative diseases, which tend to progress irreversibly and are associated with large socioeconomic and personal costs. ^[7] Because ageing is fundamental to neurodegeneration, the central biological mechanisms of ageing are potential targets for novel therapies, including NAD+ precursors, mitophagy inducers and inhibitors of cellular senescence. ^[7] Traumatic brain injury, particularly moderate to severe, is a risk factor for all-cause dementia and Parkinson's disease. ^[12] In mice, the natural polyamine spermidine postpones the manifestation of various age-associated disorders such as cardiovascular disease and neurodegeneration, making it a candidate for translational aging research. ^[13]