There were 962 million elderly (60+) globally in 2017, and this number will rise to 2.1 billion in 2050, bringing formidable healthcare and socio-economic challenges. Aging is arguably the highest risk factor for numerous human diseases, thus understanding the molecular mechanisms of human aging holds the promise to develop interventional and therapeutic strategies for many diseases all at once, promoting healthy longevity.

Accumulation of damaged mitochondria is a hallmark of human aging and age-related neurodegeneration, including Alzheimer’s disease (AD). However, the molecular mechanisms of the impaired mitochondrial homeostasis and their relationship to AD are still elusive. Mitophagy is a cellular self-clearing process of damaged and superfluous mitochondria, thereby plays a fundamental role in maintaining neuronal function and survival. We hypothesize that defective mitophagy causes accumulation of damaged mitochondria, which further in combination with the two main AD causative factors, Aβ plaques and tau tangles, exacerbating AD progression. Restoration of mitophagy through upregulation of cellular NAD+, a primary cofactor in human health and life, forestalls pathology and cognitive decline in C. elegans and mouse models of AD. In view of the physiological feature of NAD+ in human, our study suggests immediate interventional/therapeutic potential for both normal ageing and age-related memory loss.