Table 1.

Bioactive peptides with anti-aging activity.

Classification	Name and Delivery Way	Source	Rodent Model	Target Organ	Mechanism
Food-derived active peptide	Walnut protein hydrolysates(WPH) Oral gavage for 21 days Low: 333 mg/kg High: 666 mg/kg	Walnut	Alzheimer’s disease model mice aged 6–8 weeks scopolamine solution (1.0 mg/kg)	Brain	SOD↑ GSH-Px↑ CAT↑ Nrf2↑ BDNF↑ CREB↑ MDA↓ TNFα↓ AchE↓ Trp-, Tyr-, or Phe-containing peptide has high affinity to Keap1 and Ache, so it can increase the activity of NRF2 and reduce the activity of Ache, which ultimately increases antioxidant capacity and anti-inflammatory ability and leads to increased BDNF, CREB transcription [15]
	Walnut protein hydrolysate and its low-molecular-weight fraction (WPH/WPHL) Oral gavage for 21 daysWPH: 666 mg/kgWPHL: 666 mg/kg	Walnut	Alzheimer’s disease model mice aged 6–8 weeks LPS (300 μg/kg bw)	Brain	SOD↑ GSH-Px↑ CAT↑ MDA↓ TNFα↓ TNFα↓ IL-6↓ IL-1β↓ Trp, Gly, Leu residues, hydrophobic amino acids, and aromatic amino acids in polypeptides can inhibit the expression of pro-inflammatory factors TNF-α, IL-1β, and IL-6 and reduce inflammation [16]
	Tyr-Val-Leu-Leu-Pro-Ser-Pro-Ly (walnut protein hydrolysates) Continuous injection for 4 weeks 60 mg/kg bw	Walnut	Alzheimer’s disease model mice (C57BL/6) 5–6 week oldscopolamine solution (1 mg/kg bw)	Brain	ATP↑ PINK1↑ Parkin↑ NRF2↑ LC3 II/LC3 I↑ Beclin↑ KEAP1↓ p62↓ It can increase antioxidant capacity through Nrf2 signaling pathway and increase the expression of Beclin-1, Parkin, and PINK1 to enhance mitochondrial autophagy capacity [96]
	Alcalase potato-protein hydrolysates (IF) Oral administration 3 weeks 1 mg/kg bw	Potato	Senescence-Accelerated mice (SAMP8) 6 months high-fat diet	Liver/heart	pAKT↑ Sirt1↑ pAMPK↑ PGC1α↑ pFOXO3a↑ Bax↓ GOT↓ GPT↓ LDL↓ ANP↓ BNP↓ pGATA4↓ It can down-regulate cardiac hypertrophy markers ANP and BNP, reduce inflammation in the heart and liver, and reduce apoptosis by stimulating the activity of Sirt1 [97]
	Alcalase potato protein hydrolysate (APPH) Oral administration 4 weeks Low: 15 mg/kg/day Middle: 45 mg/kg/day High: 75 mg/kg/day	Potato	Sprague-Dawley (SD) rat 23 months old high-fat diet	Heart	p-p38/p38↓ GSN↓ p-Gata4↓ TGFβ↓ APPH has good lipid solubility and can reduce myocardial hypertrophy and fibrosis in aging rats through TGF-β/GSN pathway [98]
	Casein hydrolysates Continuous injection 10 weeks 200 mg/kg	Casein	Diabetic rat high-fat diet	Liver	NRF2↑ HO-1↑ SOD↑ GSH↑ MDA↓ By enhancing Nrf2 translation, the activity of antioxidant enzymes was enhanced, and the activities of DPP-IV and ACE were inhibited, among which dipeptide WM could inhibit Keap1/Nrf2 interaction [99]
	Wheat germ albumin hydrolysates ((Ala-Asp-Trp-Gly-Gly-Pro-Leu-Pro-His)) Continuous injection 1 week 4 mg/kg	Wheat	Diabetic mice 6 weeks old	Vascular	pAMPK/AMP↑ pPKCζ/PKCζ↓ NOX4↓ ROS↓ pAKT/AKT↓ Inhibition of NOX4 expression through the PKCζ/AMPK signaling pathway reduced oxidative stress levels and the release of inflammatory factors [100]
	Collagen hydrolysate Pro-Hyp Oral administration 4 weeks 210 mg/kg	Porcine skin	Chronic kidney disease mice 6 weeks old	Kidney	Liver iron content↑ EPO↑ HIF-2α↑ Hepcidin↓ TNF-α↓ IL-1β↓ IL-6↓ NF-κB↓ COX2↓ It reduces inflammation by regulating inflammatory pathways and plays a protective role in regulating HIF-2α, EPO, and Hepcidin [101]
	Anchovy hydrolysates Pro-Ala-Tyr-Cys-Ser (PAYCS) 20 days 0.2 mM/kg/day	Anchovy	Alzheimer’s disease model mice 6 weeks old Scopolamine solution (1 mg/kg bw)	Brain	Ach↑ AchR↑ Nrf2↑ BDNF↑ SOD↑ The antioxidative effects of PAYCS and PAY may be related to the Try active phenolic structure in the sequence and the hydrogen donor of the sulfhydryl group in Cys. Both active peptides have the ability to promote the binding of Ach and AchR [102]
	Soy protein isolate (SPI) Oral administration 8 weeks	Soy	Obese rat 6 weeks old	Liver	NPTX2↑ GPT↑ INMT↑ HAL↑ The increased expression of NPTX2 reduced the inflammation of the rat liver, the increased expression of GPT may be related to mitochondrial energy metabolism, the increased expression of INMT may be related to the relief of NAFLD symptoms, and the increased expression of HLT can consume excess protein in the liver [103]
	Walnut protein hydrolysate Oral administration Low: 0.32 g/L Middle: 0.96 g/L High: 2.88 g/L	Walnut	Skin-aging model rat Exposed to UV-R	Skin	Elastin↑ Fibrillin-1↑ MMP-1↓ Increasing the expression of Col I, Col III, HYP, and HA and significantly attenuated the activity of MMP-1 [104]
	Eucheuma hydrolysate (EZY-1) 28 day 0.25 mg/kg 0.5 mg/kg 1 mg/kg 50 mg/kg	Eucheuma	Pulmonary fibrosis mice (C57BL/6J) 8 weeks old injected with 3.5 mg/kg of bleomycin	Lung	T-SOD↑ GSH-Px↑ HYP↓ MDA↓ pSmad3↓ EZY- 1 is easily absorbed in the intestinal tract, and its hydrophobic point facilitates the entry of EZY-1 into cells, while EZY-1 can reduce pulmonary fibrosis through TGF-β/Samd signaling pathway. [105]
	Egg white protein hydrolysate (EWPs) Gavage 14 days Low: 50 mg/kg Middle: 100 mg/kg High: 200 mg/kg	Egg	Colitis model mice (BALB/c) administered 3% (w/v) DSS	Gut	Candidatus_Sacchar-imonas↑ norank_f_Ruminococcaceae↓ Ruminiclostridium↓ TNF-α↓ IL-6↓ IL-8↓ EWPs contain Trp, Try, His, and Met, which make it have good antioxidant activity and can reduce the release of inflammatory factors by increasing the content of Lactobacillus and Candidatus-Saccharimonas in the gut [106]
	Whey protein hydrolysate (WHP) Gavage 30 days Low: 0.3 g/kg Middle: 1.5 g/kg High: 3.0 g/kg	Egg	D-galactose-treated mice (C57BL/6N) 6 months 100 mg/kg	Brain	SOD↑ GSH-Px↑ AChE↑ p-CaMKII↑ MDA↓ TNF-α↓ IL-1β↓ TNF-α↓ WHP can reduce the release of inflammatory factors, increase the activity of antioxidant enzymes, and enhance the activities of AchE and P-CamKII, which play an important role in maintaining synaptic plasticity [107]
A peptide encrypted from the venom of Tityus serrulatus scorpion	Lys-Pro-Pro (KPP)	Scorpion	Mice 10 weeks old	Heart	pPLN/PLN↓ pERK/ERK↓ KPP regulates cellular stress-related proteins and exerts cardioprotective effects through PLN dephosphorylation [108]
Secretory bioactive peptide	Humanin (HNG) Injections 14 months 4 mg/kg	Mitochondria	Aging mice (C57BL/6N) 18 months	Heart	pAKT↑ pGSK3β↓ 4-HNE↓ TGF-β1↓ FGF-2↓ MMP-2↓ HNG down-regulated the expression of GSK-3β through Akt pathway, reduced myocardial apoptosis, down-regulated FGF-2 and MMP-2 expression, and inhibited cardiac fibrosis [109]
Peptide hormone	Melatonin Injections 30 days 10 mg/kg	Pineal gland	Aging mice 8 weeks old D-galactose 100 mg/kg	Brain	SNAP-25↑ PSD95↑ GluR1↑ p-CREB↑ ROS↓ GFAP↓ p-IKKβ↓ NF-κB↓ COX-2↓ NOS2↓ IL-1β↓ TNFα↓ p-JNK↓ Melatonin can reduce synaptic damage caused by oxidative stress and neuroinflammation through RAGE/NFκB/JNK pathway and has a good therapeutic effect on neurodegeneration [110]

Annotation: “↑” Up-regulation, “↓” Down-regulation, the abbreviations in Table 1 are all listed in Table A1.