Table 1.

Dietary anti-aging polyphenols and potential mechanisms.

Polyphenols	Source	Age-Related Conditions	Model	Dosage	Anti-Aging Activity and Proposed Anti-Aging Mechanism
Resveratrol	Grapes, red wine, peanuts, and blueberries	Age-related motor deficits	Older adults	500 mg/day, 1000 mg/day	A pilot randomized controlled trial indicates that the combined application of exercise training and resveratrol in elderly people with functional limitations could improve skeletal muscle mitochondrial function and exercise-related physical function indicators [58].
		Sarcopenic obesity	Sprague-Dawley (SD) rats	0.4% of diet	Resveratrol could ameliorate mitochondrial dysfunction and oxidative stress, thereby improving protein metabolism and helping to prevent sarcopenic obesity in the elderly [59].
		Aging	ddY mice (derived from a non-inbred strain carrying a retrovirus causing significant mortality with age)	0.4 g/kg of diet	Resveratrol could reduce the level of acetylated proteins in muscles and restore autophagic activity, thereby alleviating age-related sarcopenia and cardiomyocyte hypertrophy [60].
		Aging	HtrA2 KO mice (the absence of serine/threonine protease HtrA2 causes a PD phenotype)	25 mg/kg body weight (BW)	Resveratrol treatment can extend the lifespan of HtrA2 KO mice and delay the deterioration of the motor phenotype by attenuating apoptosis at the level of Bax [61].
		Aging	Caenorhabditis elegans (C. elegans)	100 mM	Resveratrol, as a Sirtuin activator, can simulate calorie restriction and extend the lifespan of C. elegans [62].
		Aging	Drosophila melanogaster	200 μM	Supplementation of resveratrol to larval can effectively eliminate ROS, thereby extending the adult lifespan of fruit flies and not reducing their reproductive capacity [63].
		Ovarian aging	N. guentheri	200 μg/g food	Resveratrol could delay ovarian aging by alleviating inflammation and ER stress through the SIRT1/NRF2 pathway [64].
		Aging	S. cerevisiae	10, 100, 500 μM	Resveratrol could mimic calorie restriction by stimulating Sir2, increase DNA stability, and extend lifespan by 70% in yeast [65].
		Aging	Human mononuclear cells (PBMCs)	5 µM	Compared with the elderly, resveratrol exerts better antioxidant and anti-inflammatory effects in PBMCs of middle-aged individuals [66].
		Brain aging	Hippocampal astrocytes	10 μM	Resveratrol could increase the antioxidant defense capacity and reduce pro-inflammatory cytokines in hippocampal astrocyte cultures of rats of all ages, improving NDs [67].
		Age-related motor deficits	SH-SY5Y cells	1 or 5 μM	Resveratrol alleviates age-related motor deficits by promoting the survival of dopaminergic neurons and the activation of the ERK1/2 pathway [68].
Ellagic acid	Berries, nuts, tea, and medicinal plants [69]	Aging	D-gal-induced aging rats	120 mg/kg BW	EA improved oxidative damage and inflammation in D-gal-induced aging rats [70].
		Hepatic lipid metabolism disorders induced by aging	25-month-old rats	30 mg/kg BW	EA affected lipid metabolism in the aged liver via the sirt1/AMPK/sreBP-1c/PPAr-α pathway for age-related metabolic disorders [71].
		Brain aging	SD rats	10, 30, 90 mg/kg BW	EA could increase the proliferation of brain neural stem cells and protect brain cell activity through the Wnt/β-catenin signaling pathway to help treat nerve dysfunction, NDs, and aging [72].
		Osteoporosis	C57BL/6 mice, bone mesenchymal stem cells	Mice: 10, 50 mg/kg BW; cell: 0 μM–30 μM	EA could promote bone formation by activating the SMAD2/3 signaling pathway to ameliorate aging-induced osteoporosis [73].
		Skin aging	Male SKH-1 hairless mice, human dermal fibroblasts	Mice: 10 μmol/L, cell: 1–10 μmol/L	EA could reduce wrinkles and UV-induced skin inflammation to improve photoaging by decreasing UV-B-induced collagen degradation and inflammatory reactions [74].
		Aging	C. elegans	50 μM	EA reduced the injury caused by UV radiation and enhanced stress resistance to extend the lifespan of C. elegans [75].
		Aging	Drosophila melanogaster	100 μM and 200 μM	EA can up-regulate the expression of dFOXO, CAT, and SOD, thereby extending lifespan [76].
		Aging	SH-SY5Y cells	0.1–1 μM	Lower concentrations of EA could provide better anti-aging benefits than higher concentrations of EA and metformin, presumably via the PPAR-γ/ HO-1 signaling pathway [77].
		Skin sagging and wrinkling	Human dermal fibroblasts	2 μg/mL	EA improved skin extracellular matrix production of elastin and collagen and improved skin fine wrinkles [78].
Urolithin A	Gut microbiota metabolite of EA	Aging	Healthy elderly male and female	250, 500, 1000 and 2000 mg	UA could promote mitochondrial autophagy and improve muscle health in old animals and in preclinical models of aging [79].
		Aging	D-gal-induced aging mice	3, 15 mg/kg BW	Uro-A from the colon can prevent D-gal-induced aging in mice by blocking NF-κB and mTOR targets, improving motor and cognitive abilities [80].
		Alzheimer’s disease (AD)	3xTg-AD mice, B6129SF2/J mice	5 mg/kg BW	UA could improve the cognition of 3xTg-AD mice and prolong longevity in normal aging mice by inducing autophagy and increasing amyloid-β (Aβ) clearance in neuronal cells [81].
		Aging	C. elegans, C57BL/6 mice	C. elegans: 50 μM, mice: 50 mg/kg BW	Urolithin A could induce mitophagy and improve mitochondrial and muscle function in C. elegans and rodents, leading to life extension [82].
		Brain aging	H2O2-induced PC12 cell, D-gal-induced aging mice	Cell: 10, 30, 50 μg/mL, Mice: 50, 100, 150 mg/kg body weight	Urolithin A can exert neuroprotective effects and delay brain aging by activating miR-34a-mediated SIRT1/mTOR signaling pathway [83].
		Aging	D-gal-induced aging mice	50, 100, 150 mg/kg BW	UA could attenuate D-gal-induced liver injury in aged mice via antioxidant, anti-inflammatory, and anti-apoptotic properties [84].
Gallic acid	Rheum palmatum, Eucalyptus robusta, Cornus officinalis	Age-associated thymic involution	D-gal-treated mice	200, 250, 500 mg/kg body weight	GA administration may ameliorate age-related thymic degeneration and enhance immune function in the elderly by stimulating FoxN1 expression, increasing proliferating cells, and decreasing apoptotic cells [85].
		Aging	H2O2-induced rat’s embryonic fibroblast cells	1000 μM	GA could postpone aging through its antioxidative stress potential and modulation of mitochondrial complexes’ activities [86].
		AD	APP/PS1 transgenic AD mouse model	20 mg/kg body weight	EA could inhibit neuroinflammation and stabilize brain oxidative stress [87].
Rutin	Fagopyrum esculentum, Ruta graveolens, and Sophora japonica [88]	Aging	Drosophila melanogaster	200 μM and 400 μM	Rutin could improve the resistance of male and female Drosophila melanogaster fed with a high-fat diet, increase the expression of age-related genes, and extend longevity [89].
		Huntington’s disease	C. elegans	15, 30, 60, 120 μM	Rutin could inhibit polyglutamine protein aggregation in muscle, decrease neuronal death, and extend longevity through antioxidant, autophagy, and insulin/IGF1 signaling pathways [90].
		Aging	D-gal-treated mice	50 mg/kg body weight	Rutin could enhance the biochemical indicators of aging rats by exerting antioxidant effects and regulating apoptosis-related proteins to inhibit cell apoptosis [91].
		Age-related metabolic dysfunction	Twenty-month-old rats	25, 50 mg/kg body weight	Rutin suppresses aging-associated mitochondrial dysfunction, endoplasmic reticulum stress, and oxidative stress, thus improving the response to age-related metabolic dysfunction [92].
		AD	TgAPP mice (a model for AD)	30 mg/kg body weight	Rutin could raise GSH/GSSG levels, reduce MDA levels, and inhibit APP expression and BACE1 activity, resulting in anti-AD and anti-aging benefits [93].
Quercetin	Grapes, peaches, onions, garlic [94]	Age-related metabolic dysfunction	Twenty-one-month-old mice	Dasatinib (5 mg/kg BW) and quercetin (50 mg/kg BW)	Dasatinib + quercetin (D + Q) lowers inflammation in adipose tissue and enhances systemic metabolic function in older people [95].
		Age-dependent progression of disc degeneration	C57BL/6 mice	Dasatinib (5 mg/kg BW) and quercetin (50 mg/kg BW)	D + Q can target senescent cells non-invasively and lessen the impact of age-dependent degeneration [96].
		Aging	Macaca fascicularis	Dasatinib (5 mg/kg BW) and quercetin (50 mg/kg BW)	D + Q could prevent aging by strengthening the gut barrier, boosting immunity, and combating inflammation [97].
		Aging	C57BL/6 mice	Dasatinib (5 mg/kg BW) and quercetin (50 mg/kg BW)	D + Q could lead to selective elimination of senescent cells and the release of senescence-associated pro-inflammatory cytokines [98].
		Intestinal senescence	BALB/c mice	Dasatinib (5 mg/kg BW) and quercetin (50 mg/kg BW)	Long-term D + Q treatment could decrease the gene expression of senescence and inflammation to alleviate intestinal senescence [9].
Naringenin	Ribes meyeri	Aging	C57BL/6 mice	25, 50, 100 mg/kg BW	Naringenin could reduce neuronal damage and mitigate systemic inflammation induced by LPS by modulating the expression of NF-κB/TNFα/COX-2/iNOS/TLR4/GFAP [99].
		Retinal degeneration	C57BL/6 mice	100 mg/kg BW	Oral administration of naringenin could regulate mitochondrial dynamics and autophagy to counteract aging-related retinal degeneration [100].
		Aging	C. elegans, 6-month-old C57BL/6J mice	C. elegans: 100 μM, mice: 100 mg/kg BW	Naringenin could extend the lifespan of C. elegans and slow brain aging in mice by increasing the expression of SIRT enzymes, promoting the activity of metabolic enzymes, and upregulating the expression of anti-aging markers [101].
Cyanidin-3-O-glucoside (Cy3G)	Vegetables and berries [102]	AD	HMC3 cell, APPswe/PS1ΔE9 mice (a model for AD)	cell: 50 μM, mice: 30 mg/kg BW	Cy3G could eliminate accumulated β-amyloid and modulate microglial polarization by activating PPARγ and promoting Aβ42 phagocytosis through TREM2 overexpression [103].
		AD	APPswe/PS1ΔE9 mice	30 mg/kg BW	Cy3G could reduce lysosome-associated protein expression, increase autophagy, and modulate the PI3K/Akt/GSK3β signaling pathway to protect neurons and enhance cognitive performance in AD mice [104].
		AD	SD rats received Aβ in the hippocampus	10 mg/kg BW	Cy3G could attenuate Aβ-induced tau protein hyperphosphorylation and GSK-3β hyperactivation, possibly rescuing Aβ-induced cognitive deficits through GSK-3β/tau variation [105].
		AD	APPswe/PS1ΔE9 mice	30 mg/kg BW	Cy3G may exert therapeutic effects on AD through antioxidant and immunomodulatory mechanisms [106].
		Parkinson’s disease (PD)	MPTP-induced C57BL/6J	10, 20, 40 mg/kg BW	Cy3G could play a role in the treatment of PD by modulating the structure and metabolism of gut microbiota [107].
		Aging	C. elegans	12.5, 25, 50 μg/mL	Cy3G could enhance resistance and extend the lifespan of polystyrene-exposed C. elegans through the DAF-16 pathway [108].
		Aging	H9c2 cells	1 mM	Cy3G could decrease CD38 expression, increase Sirt6 expression in tissues, and restore NAD+ and NK cell levels to exert anti-aging effects through CD38-Sirt6 signaling [109].
Procyanidin C1 (PCC1)	Grape seed extract	Aging	PSC27 cells, WI38 cells, HUVEC cells; C57BL/6J mice	Cell: 1, 5, 10 μg/mL Mice: 20 mg/kg BW	Low concentrations of PCC1 can inhibit the formation of SASP, while at higher concentrations, it may selectively kill senescent cells by promoting the production of ROS and mitochondrial dysfunction [110].
		Aged retina	Aged mice	8 mg/kg of diet	Long-term PCC1 treatment could relieve function and structural impairment in the aged retina and reduce the accumulation of senescent cells and secretion of SASP [111].
Nordihydroguaiaretic acid	Larrea tridentata	Aging	UM-HET3 mice (designed to model the aging process and age-related diseases)	2.5, 5 g/kg of diet	Nordihydroguaiaretic acid could increase the survival rate of male mice but does not change the survival rate of female mice, which might be explained by gender differences in steady-state levels or drug metabolism [112].
Pterostilbene	Blueberries	AD	Senescence accelerated mouse prone 8 (SAMP8) mice	120 mg/kg of diet	Pterostilbene could increase the expression of peroxisome proliferator-activated receptor (PPAR) α, improve cognitive function and cellular stress regulation ability, and alleviate AD symptoms [113].
		AD	18-month-old rats	22.5 mg/kg BW	Pterostilbene could increase the expression of postsynaptic density protein 95 and improve the cognitive ability of elderly rats with mild cognitive impairment AD [114].
		AD	19-month-old male Fischer	40, 160 mg/kg of diet	Pterostilbene can effectively reverse cognitive behavioral deficits and dopamine release and improve age-related cognitive degeneration [115].