Flavonoids-Natural Gifts to Promote Health and Longevity

Abstract

The aging of mammals is accompanied by the progressive atrophy of tissues and organs and the accumulation of random damage to macromolecular DNA, protein, and lipids. Flavonoids have excellent antioxidant, anti-inflammatory, and neuroprotective effects. Recent studies have shown that flavonoids can delay aging and prolong a healthy lifespan by eliminating senescent cells, inhibiting senescence-related secretion phenotypes (SASPs), and maintaining metabolic homeostasis. However, only a few systematic studies have described flavonoids in clinical treatment for anti-aging, which needs to be explored further. This review first highlights the association between aging and macromolecular damage. Then, we discuss advances in the role of flavonoid molecules in prolonging the health span and lifespan of organisms. This study may provide crucial information for drug design and developmental and clinical applications based on flavonoids.

Keywords: aging; flavonoids; health span; macromolecular damage.

Figure 1

Basic structures of the major naturally occurring flavonoids.

Figure 2

Diagram of the major influences and mechanisms by which macromolecular damage induces aging. Damage insults (genotoxic stress, oxidative stress, etc.) in genetic or environmental factors damage macromolecules (mainly including DNA, proteins, and lipids) during the aging process, causing intracellular damage to accumulate. At the same time, the repairability in the cell declines with aging, which causes the accumulation of unrepaired damage in the cell. Accumulated unrepaired damage can lead to mutations or chromosomal aberrations, leading to genome instability. Severely shortened telomeres activate the DNA repair and damage response (DDR) and cause cell senescence. Accumulated unrepaired damage affects autophagy and the ER-UPR and results in the loss of protein complex stoichiometry. Mitochondrial dysfunction is driven by NAD+ deprivation caused by nuclear DNA repair, mitochondrial autophagy defects induced by DNA damage, and changes in the expression of mtDNA polymerase that affect mtDNA replication. The accumulated unrepaired damage wreck the nutrient-sensing pathway, affecting repair and signal transduction. The accumulated unrepaired damage induces cell senescence and leads to the exhaustion of the stem cell pool through DDR-induced apoptosis, senescence, premature differentiation, and changes in the niche of stem cells. Cell senescence affects cell-to-cell communication through inflammatory cytokines and inhibitory growth signals.

Figure 3

Flavonoids work on each type of damage-dependent trigger of cellular senescence. Cells induced to senesce by damaging insults exhibit higher basal levels of damage than healthy cells and generate damage at a higher rate.