Table 2.

Effect of resveratrol on age-related diseases.

Study type	Subjects	Administration methods	Dose & duration	Effects and mechanisms	Ref.
Neurodegenerative diseases
In vivo	C57BL/6J mice	Intraventricular injection	5 μg/μL for 1 week	Improved learning and memory functions in a Sirt1-dependent way	[33]
In vivo	Aged C57BL/6 mice	Oral administration	200 mg/kg for 10 days	Rescued cortical neurovascular coupling responses to improve neuronal activity and function by restoring cerebromicrovascular endothelial function and decreasing ROS production	[65]
In vivo	C57BL/6 mice	Intraperitoneal injection	100 mg/kg for 7 days	Alleviated the hippocampus-dependent cognitive impairment via anti-inflammation and antiapoptosis actions	[66]
In vivo	Male F344 rats	Intraperitoneal administration	40 mg/kg for 4 weeks	Improved memory and mood functions, increased hippocampal neurogenesis and microvasculature, and reduced glial activation	[34]
In vivo	Old male rats	Chronic administration	20 mg/kg for 4 weeks	Improved cognitive impairment by enhancing the secretion of neurotransmitters (serotonin, noradrenaline, and dopamine), which is largely due to the increased activities of TPH and TH	[35]
In vitro, in vivo	Adult hippocampal precursor cells; female Balb/C mice	Cell culture; injection	40 mg/kg for 2 weeks	Induced neuronal differentiation in adult hippocampal precursor cells without effects on proliferation in vitro, improved behavioral performance, increased production of new neurons, elevated population of doublecortin-expressing intermediate cells, and promoted hippocampal neurogenesis in vivo through the phospho-Akt and phosphoprotein kinase C signaling pathways	[32]
In vivo	Aged Sprague-Dawley rats	Intraperitoneal injection	100 mg/kg for 7 days	Inhibited neuronal apoptosis and improved behavioral performance via Sirt1-p53 signaling pathway	[67]
In vivo	Male Wistar rats	Oral administration	50 mg/kg for 12 weeks	Improve aging-induced emotional and spatial learning memory impairment via inhibiting inflammation	[36]
In vitro, in vivo	SH-SY5Y neuroblastoma cells; male C57BL/6 mice	Cell culture; feeding	1 or 5 μM; 120 mg/kg	Alleviated age-related motor decline and exerted neuroprotection via the promotion of dopamine neuronal survival and activation of the ERK1/2 pathways	[68]
Cardiovascular disease
In vitro	Aging endothelial cells; aortas of old WKY rats	Cell and tissue culture	10 μmol/L	Inhibited S6K1 signaling, reduced superoxide generation, and enhanced NO levels	[39]
In vivo	Senescence-accelerated mice prone 8 (SAMP8)	Intraperitoneal injection	20 mg/kg for 3 days	Attenuated doxorubicin-induced cardiotoxicity through restoring the activity of Sirt1	[42]
In vivo, in vitro	Aged male C57BL/6 mice; vascular smooth muscle cells	Dietary supplementation	40 mg/kg for 6 months	Lowered aorta media thickness, inflammation, fibrosis, and oxidative stress and protected against arterial aging through modulating the activity of the renin-angiotensin system	[43]
In vivo	Wistar albino rats	Drinking water	0.05 mg/mL for 6 weeks	Altered vessel responsiveness and biomarkers related to vascular functions	[69]
In vitro	Human umbilical vein endothelial cells	Cell culture	10 μM	Enhanced the cell viability and SOD levels, inhibited the increased levels of senescence-associated β-galactosidase and intracellular ROS induced by H2O2 treatment, and upregulated autophagy	[40]
In vitro	Thoracic aorta of aged Wistar rats	Organ culture	30 μM for 4 h or 24 h	Improved methylglyoxal-induced endothelial dysfunction by increasing eNOS expression and activity	[41]
Sarcopenia
In vivo	Fischer 344 x Brown Norway rats	Dietary supplementation	50 mg/kg for 6 weeks	Protected against aging-induced muscle loss via modestly altered key mitochondrial regulatory and apoptotic signaling pathways in glycolytic muscle	[47]
In vivo	Fischer 344 x Brown Norway rats	Oral gavage	125 mg/kg	Improved muscle mass, increased the fiber cross-sectional area of type IIA and IIB fibers during reloading after hindlimb suspension due to decreases in the abundance of proapoptotic proteins	[48]
In vivo	Aged C57BL/6J mice	Oral gavage	25 mg/kg BW for 4 weeks	Resveratrol combined with exercise training showed stronger muscle strength and endurance performance of aged mice than the resveratrol or exercise training alone	[49]
In vivo	Aged male Sprague-Dawley rats	Dietary supplementation	150 mg/kg for 6 weeks	Increased the relative grip strength and muscle mass and reduced the increment in sarcomere length, I-band, and H-zone via antiapoptotic signaling pathways through the activation of AMPK/Sirt1	[51]
In vivo	C57/BL6 mice	Dietary supplementation	0.04% for 6 months	Inhibited tubular aggregates and showed better resistance to fatigue	[70]
In vivo	C57BL/6J male mice	Dietary supplementation	0.04% for 6 months	Showed a better fatigue resistance	[71]
Cancers
In vitro	Ovarian cancer cells	Cell culture	25-800 μM	Suppressed proliferation and evoked apoptosis via inhibiting glycolysis and targeting AMPK/mTOR signaling pathway	[53]
In vitro	Gastric cancer cell	Cell culture	0, 25, 50, and 100 μM for 96 h	Inhibited cell proliferation and survival through inhibition of PIM-1 kinase activity	[54]
In vitro	Human prostate cancer cell lines	Cell culture	50 μM for 48 h	Inhibited cell proliferation and migration through the NF-κB pathway	[55]
In vitro, in vivo	Colon cancer cells; nude mice	Cell culture; intraperitoneal injection	0-240 μmol/L; 150 mg/kg BW	Inhibited invasion and metastasis through the reversal of EMT via the Akt/GSK-3 β/Snail signaling pathway	[56]
In vitro	Human colon cancer cell lines	Cell culture	0-50 μM	Inhibited cell viability, induced apoptosis, and decreased expression of cyclooxygenase-2 and prostaglandin receptor	[57]
In vitro	Prostate cancer cells	Cell culture	25-100 μM	Inhibited proliferation and promoted apoptosis	[58]
Other diseases
In vitro	Mouse oocytes	Cell culture	1 μM	Improved the quality of postovulatory aging oocytes via maintaining mitochondrion distribution and the normal morphology of spindle, alleviating oxidative stress, ameliorating apoptosis, and decreasing the loss of sperm binding	[60]
In vivo	Female C57BL/6 mice	Drinking water	30 mg/L for 6 or 12 months	Reserved the ability of reproduction and showed a larger follicle pool, improved the number and quality of oocytes, telomerase activity, telomere length, and age-related gene expression in ovaries	[61]
In vivo	Aged male Wistar rats	Drinking water	10 mg/kg for 10 weeks	Increased bone volume, bone trabecular number, and cortical thickness and reduced spacing between trabeculae	[63]
In vivo	C57BL/6 mice	Dietary supplementation	300 mg/kg for 10 weeks	Accelerated osteoblast activity and bone growth, and promoted bone formation in a Sirt1-dependant way	[64]

Note: Sirt1: sirtuin1; ROS: reactive oxygen species; TPH: tryptophan hydroxylase; TH: tyrosine hydroxylase; Akt: protein kinase B; ERK1/2: extracellular-regulated kinases 1 and 2; S6K1: ribosomal protein S6 kinase, polypeptide1; NO: nitric oxide; SOD: superoxide dismutase; eNOS: endothelial nitric oxide synthase; AMPK: 5′-monophosphate-activated protein kinase; mTOR: mammalian target of rapamycin; PIM-1 kinase: proviral integration site for Moloney murine leukemia virus-1 kinase; BW: body weight; NF-κB: nuclear-factor kappa B; EMT: epithelial-mesenchymal transition; Akt/GSK-3 β/Snail: protein kinase B/glycogen synthase kinase-3 β/Snail signaling.