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Flavonoids are efficacious candidates as pharmaceuticals or nutraceuticals in the treatment of Alzheimer's disease (AD), aging and other age-related chronic inflammatory diseases. Natural flavonoids reduce pathological hallmarks, extracellular amyloid deposits and neurofibrillary tangles by mediating amyloid precursor protein (APP) processing, Aβ accumulation and tau pathology. The antioxidant and anti-inflammatory actions as well as modulation of sirtuins and telomeres are also involved in the amelioration of aging, neurodegeneration and other age-related diseases. Recently, some flavonoids were shown to inhibit poly (ADP-ribose) polymerases (PARPs) and cyclic ADP-ribose (cADP) synthases (CD38 and CD157), elevate intracellular nicotinamide adenine dinucleotide+ (NAD+) levels and activate NAD+ dependent sirtuin −mediated signaling pathways. We summarized how flavonoids reduce the degradation of NAD+ with an emphasis on the mechanisms through which flavonoids affect the NAD+-sirtuin axis to protect against AD. Aging and age-related diseases as well as a decline in the physiological reserve are the risk factors for cognitive frailty. Flavonoids with multiple therapeutic targets may also be potential candidates for the prevention and treatment of cognitive frailty.Flavonoids activate NAD+ dependent SIRT1 and SIRT3 by inhibiting PARP-1 and CD38 and are promising therapeutic interventions for AD and cognitive frailty. SIRT1 activation protects against AD pathology. Increased SIRT1 and SIRT3 activity decreases neurovascular inflammation and oxidative damage and improves glucose and lipid metabolism. Flavonoids directly inhibit AChE and BuChE. Cognitive frailty can result from (pre-) physical frailty with the presence of reversible or potentially reversible cognitive impairment due to age-related diseases (Pre-MCI or MCI due to non-AD), and from (pre-) physical frailty with the presence of pre-clinical AD or MCI due to AD.