1. Introduction

In recent history, human life expectancy has continuously risen, and the proportion of the elderly population has sharply increased with the improvement of medical technology. Dysfunction of normal biological processes accompanies aging, and the acceleration of molecular damage and dysfunction in cells, tissues, and organs eventually leads to aging-related diseases, such as cardiovascular diseases, nutritional metabolic diseases, and cognitive disorders ^[1][2][1,2]. However, the aging process is adjustable, albeit irreversible, and scientific approaches can regulate the speed of aging and promote good health [3]. Therefore, development of efficient strategies to manage aging is critical for community health. In recent years, a growing body of work has aimed to test several hypotheses related to the molecular mechanisms that play critical roles in determining longevity. Among them, reactive oxygen species (ROS) inducing oxidative stress is considered one of the primary contributors to aging [4]. Hence, exploration of substances with antioxidant activity is an important strategy for the management of aging ^[5][6][5,6]. Many kinds of anti-aging drugs have been synthesized and tested in clinical trials, but many obstacles prevent drug development, including the adverse reactions of the human body to synthesized drugs. Therefore, natural active substances with high efficiency and low side effects are important alternatives for combating aging [6].

Recently, natural bioactive peptides have attracted special attention. Biologically active peptides with anticancer, anticoagulant, antidiabetic, antihypertensive, antimicrobial, antioxidant, and cholesterol-lowering properties have been reported in the biomedicine and pharmaceutical biotechnology literature [7]. Some of these compounds also exhibit notable antiaging activity in vitro or in vivo. Presently, potential bioactive peptides are mainly isolated and identified in different food products like milk, soy, rice, meat, fish, lobsters, crabs, and shrimp [8]. Some bioactive peptides are extremely safe, easily absorbed, and have no toxic side effects ^[9][10][9,10]. Moreover, because of their hypo-allergenicity characteristics, bioactive peptides have been explored as a method to treat patients with food allergies [11]. Therefore, bioactive peptides should be considered as excellent alternatives for anti-aging treatment.

Marine organisms contain high-quality functional protein or peptides with diverse molecular structures, and are an important source of new compounds, especially for China with its 18,000 km coastline, compared to terrestrial resources [12]. Presently, excluding various fish that are widely used as food materials, there is only limited use of marine protein resources from other species, such as sea cucumber, sea urchin, mussels, and several kinds of algae. Some marine bioactive peptides regulate free radical homeostasis in vitro and in vivo, and can have antiaging effects in cell and animal models and in human clinical trials ^{[13][14][15][16]}[13,14,15,16]. Marine natural bioactive peptides have also been used in cosmeceutical skin products as antiaging agents ^[17][18][19][17,18,19].

2. Antiaging Activity of Peptides from the Ocean

ROS are highly reactive substances, and overproduction of ROS can result in DNA mutation, lipid, and protein dysfunction, and, ultimately, aging [20]. Thus, the main protective strategy to slow aging is to scavenge the excessive ROS by providing antioxidant agents, as well restoring the antioxidant defense system in cells. In the human body, the antioxidant defense system consists mainly of antioxidant peptides, including carnosine, glutathione, and antioxidant enzymes, including superoxide dismutase (SOD), glutathione oxidase (GHS-Px) and catalase (CAT).

3. The Mechanisms Underlying Antiaging Activity

Marine antiaging peptides have been shown to act in several different ways, including scavenging free radical capacities in vitro, inhibiting cell apoptosis, prolonging the life span of fruit flies and nematodes, and ameliorating D-galactose levels that induce aging in mice, and have shown promise as antiaging agents in human clinical trials.

Antioxidant enzymes are an important target of peptides in cells and organisms. The underlying mechanisms involved include regulation of the classical antioxidant gene Klotho and the Keap1/nuclear fac-tor erythroid 2-related factor 2- antioxidant responsive element (Nrf2-ARE) signaling pathway. In addition, marine peptides can regulate DAF-16/FOXO-SOD-3 expression, i.e., a forkhead transcription factor/forkhead transcription factors of the O class, which can enhance antioxidant enzyme activity.

The antiaging properties of the Leu-Cys-Gly-Glu-Cys peptide have been verified in healthy mouse models. After treatment with the peptides, mice display a healthier status based on a series of body indices, such as increased body weight and decreased liver and brain indices. Based on the analysis of liver and serum samples, the peptide was found to increase the activity of serum GSH-Px and SOD and decrease levels of MDA. Additionally, the transcription levels of Keap1 and Nrf2 were significantly downregulated in the liver and brain. These results confirmed that marine bioactive peptides can be used as potential regulators of aging in cells and mice, extending the earlier findings that showed it can scavenge free radicals in vitro. These results also highlight the importance of the Keap1/Nrf2-ARE pathway in antiaging ^[28][52].

As summarized in Table 1 , marine antioxidant peptides have potential as antiaging agents because they can protect cells from oxidative stress by directly scavenging excess free radicals. In addition, marine peptides can inhibit apoptosis via two pathways: the p53-Bax/Bcl-2 (BCL2-associated X protein/B lymphoblastic cells) pathway and the Mammalian target of rapamycin complex 1 (mTORC1)-mTOR-Bcl/Bax pathway.

Table 1. Marine antiaging peptides and their free radical scavenging activity in vitro.

Source	Sequences	Activities (EC50)	Ref.
Microorganism
Chlorella vulgaris	favourzyme hydrolysates	Superoxide3 (0.323 mg/mL), Hydroxyl2 (0.139 mg/mL)	[29][25]
Spirulina sp.	Thr-Met-Glu-Pro-Gly-Lys-Pro	Inhibition of ROS production	[30][26]
Dunaliella salina	Ile-Leu-Thr-Lys-Ala-Ala-Ile-Glu-Gly-Lys Ile-Ile-Tyr-Phe-Gln-Gly-Lys Asn-Asp-Pro-Ser-Thr-Val-Lys Thr-Val-Arg-Pro-Pro-Gln-Arg	DPPH1	[31][27]
Penicillium brevicompactum	N-cinnamoyl tripeptide	Hydroxyl2 (equivalent to that of quercetin at 0.1 mM)	[32][28]
Kocuria marina	Phe-Glu, Asp-Ile, Ser-Ser-Gln, Leu-Glu	DPPH1 (0.24 mg/mL)	[33][29]
Marine invertebrates
Neptunea arthritica cumingii	Tyr-Ser-Gln-Leu-Glu-Asn-Glu-Phe-Asp-Arg	DPPH1 (0.77 mM)	[34][30]
	Tyr-Ile-Ala-Glu-Asp-Ala-Glu-Arg	DPPH1 (1.04 mM)
Tergillarca granosa	Glu-Met-Gly-Pro-Ala	DPPH1 (0.53 ± 0.02 mg/mL), Hydroxyl2 (0.47 ± 0.03 mg/mL), Superoxide3 (0.75 ± 0.04 mg/mL), ABTS4(0.96 ± 0.08 mg/mL), Inhibition of lipid peroxidation	[35][31]
	Trp-Pro-Pro-Asp	DPPH1 (0.36 ± 0.02 mg/mL), Hydroxyl1 (0.38 ± 0.04 mg/mL), Superoxide3 (0.46 ± 0.05 mg/mL), ABTS4 (0.54 ± 0.03 mg/mL), Inhibition of lipid peroxidation
Brachionus rotundiformis	Leu-Leu-Gly-Pro-Gly-Leu-Thr-Asn-His-Ala,	DPPH1 (189.8 µM)	[36][32]
	Asp-Leu-Gly-Leu-Gly-Leu-Pro-Gly-Ala-His	DPPH1 (167.7 µM)
Fish
Muscle of Scomberomorous niphonius	Pro-Glu-Leu-Asp-Trp	DPPH1 (1.53 mg/mL), Hydroxyl2 (1.12 mg/mL), Superoxide2 (0.85 mg/mL), Inhibition of lipid peroxidation, Protection of plasmid DNA	[37][33]
	Trp-Pro-Asp-His-Trp	DPPH1 (0.70 mg/mL). Hydroxyl2 (0.38 mg/mL) Superoxide3 (0.49 mg/mL). Inhibition of lipid peroxidation, Protect plasmid DNA.
	Phe-Gly-Tyr-Asp-Trp-Trp	DPPH1 (0.53 mg/mL), Hydroxyl2 (0.26 mg/mL), Superoxide3 (0.34 mg/mL). Inhibition of lipid peroxidation,
	Tyr-Leu-His-Phe-Trp	DPPH1 (0.97 mg/mL), Hydroxyl2 (0.67 mg/mL), Superoxide3 (1.37 mg/mL), Inhibit lipid peroxidation.
Skin of Scomberomorous niphonius	Pro-Phe-Gly-Pro-Asp	DPPH1 (0.80 mg/mL), Hydroxyl2 (0.81 mg/mL), Superoxide3 (0.91 mg/mL, ABTS4 (0.86 mg/mL), FRAP and Inhibition of lipid peroxidation	[38][34]
	Pro-Tyr-Gly-Ala-Lys-Gly	DPPH1 (3.02 mg/mL), Hydroxyl2 (0.66 mg/mL), Superoxide3 (0.80 mg/mL), ABTS4 (1.07 mg/mL), FRAP and inhibit lipid peroxidation
	Tyr-Gly-Pro-Met	DPPH1 (0.72 mg/mL), Hydroxyl2 (0.88 mg/mL), Superoxide3 (0.73 mg/mL), ABTS4 (0.82 mg/mL), FRAP and inhibit lipid peroxidation
Cartilage of Dasyatis akajei	Ile-Glu-Glu-Glu-Gln	DPPH1 (4.61 mg/mL), Hydroxyl2 (0.77 mg/mL), Superoxide3 (0.08 mg/mL), ABTS4 (0.15 mg/mL).	[39][23]
	Ile-Glu-Pro-His	DPPH1 (1.90 mg/mL,), Hydroxyl2 (0.46 mg/mL), Superoxide3 (0.17 mg/mL), ABTS4 (0.11 mg/mL), Lipid peroxidation inhibition activity.
	Leu-Glu-Glu-Glu-Glu	DPPH1 (3.69 mg/mL), Hydroxyl2 (0.70 mg/mL), Superoxide3 (0.15 mg/mL), ABTS4 (0.19 mg/mL), Fe2+-chelating ability.
	Val-Pro-Arg	DPPH1 (4.01 mg/mL), Hydroxyl2 (1.30 mg/mL), Superoxide3 (0.16 mg/mL), ABTS4 (0.18 mg/mL).
Head of Katsuwonus pelamis	Trp-Met-Gly-Pro-Tyr	DPPH1 (0.33 mg/mL), Hydroxyl2 (0.43 mg/mL), Superoxide3 (0.38 mg/mL), FRAP and lipid peroxidation inhibition.	[40][35]
	Trp-Met-Phe-Asp-Trp	DPPH1 (0.31 mg/mL), Hydroxyl2 (0.30 mg/mL), Superoxide3 (0.56 mg/mL), FRAP and lipid peroxidation inhibition.
	Glu-Met-Gly-Pro-Ala	DPPH1 (0.46 mg/mL), Hydroxyl2 (0.52 mg/mL), Superoxide3 (0.71 mg/mL), FRAP and lipid peroxidation inhibition.
Salmon gelatin	Gly-Gly-Pro-Ala-Gly-Pro-Ala-Val, Gly-Pro-Val-Ala, Pro-Pro and Gly-Phe	Oxygen radical absorbance capacity (ORAC, 540.94 ± 9.57 µmol TE/g d.w.)	[41][36]
Pacific cod skin gelatin	Leu-Leu-Met-Leu-Asp-Asn-Asp-Leu-Pro-Pro	Scavenging the intracellular ROS	[42][37]
Jumbo squid (Dosidicus gigas, squid) skin gelatin	Phe-Asp-Ser-Gly-Pro-Ala-Gly-Val-Leu Asn-Gly-Pro-Leu-Gin-Ala-Gly-Gln-Pro-Gly-Glu-Arg	Inhibition of oxidant stress; Lipid peroxidation inhibition (>Vit. E).	[43][38]
Whole body of Parastromateus niger	Ala-Met-Thr-Gly-Leu-Glu-Ala	DPPH1 (54%), Metal chelating (78.6%) at 1 mg/mL	[44][24]
Smooth hound viscera (sharks)	Protein hydrate containing Gly, Glx, Lys, Asx, Arg, Pro and Ala	DPPH1, Inhibition of linoleic acid oxidation, Hydroxyl2.	[45][39]
Hoki (Johnius belengerii) frame	Glu-Ser-Thr-Val-Pro-Glu-Arg-Thr-His-Pro-Ala-Cys-Pro-Asp-Phe-Asn	DPPH1 (41.37 µM), Hydroxyl2 (17.77 µM), Peroxyl radical scavenging (18.99 µM), Superoxide3 (172.10 µM).	[46][40]
Limanda aspera frame	Arg-Pro-Asp-Phe-Asp-Leu-Glu-Pro-Pro-Tyr	Inhibition of linoleic acid autoxidation	[47][41]
Tuna backbone	Val-lys-Ala-Gly-Phe-Ala-Trp-Thr-Ala-Asn-Gln-Gln-Leu-Ser	Inhibited lipid peroxidation, Quenched free radicals (DPPH, hydroxyl and superoxide)	[48][42]
Frame of Theragra chalcogramma	Leu-Pro-His-Ser-Gly-Tyr	Hydroxyl2 (35% at 53.6 µM)	[49][43]

Note: DPPH¹-DPPH radical scavenging capacity, Hydroxyl²-Hydroxyl radical scavenging capacity, Superoxide³-Superoxide anion radical scavenging capacity, ABTS⁴-ABTS cation radical scavenging capacity.

As shown in Table 2 , recent investigations have focused on the impact of marine peptides on gut microbiota. The test substances have included protein hydrolysates, polypeptide fractions, and pure antioxidant peptides. Significant positive effects have been observed in many assays using peptides from microalgea, invertebrates, and byproducts of the fishing industry, such as the milt, roe and viscera of fish. Even glycosylated fish has been shown to have positive results. The balance of gut microbiota populations significantly improves not only in healthy mice or rats, but also in unhealthy ones subject to fatigue, alcohol-induced injury, and high-fat diet (HFD). In addition, a peptide combined with calcium significantly increases the abundance of beneficial gut microbes, including Firmicutes and Lactobacillus , in low-calcium diet-fed rats. Calcium absorption also increased in these animals.

Table 2. Regulation of gut microbiota by marine peptides.

4. Conclusions and Perspectives

The potential antiaging activities of natural peptides from underused marine organisms have been investigated in vitro, in cells, in animal models and in human clinical trials. These peptides act using the following molecular mechanisms: free radical scavenging, enhancing oxidase activity, protecting mitochondria, downregulating the apoptotic pathway, inhibiting MMP-1 expression, and restoring intestinal homeostasis. These results suggest that underused marine peptides have great potential as functional food and cosmetic ingredients for antiaging purposes. However, presently, there are three major outstanding issues. First, relevant research reports in the Web of Science database are few, and not enough animal assays have reported. We therefore focused on in vitro assays for this review. Second, in the limited literature, very few marine species have been explored, and vast marine protein resources are still underutilized. Third, apart from several applications in skin aging, there is a dearth of information about marine peptides in human clinical trials related to antiaging. This lack of literature makes it difficult to apply and transform these peptides for the market. To address these issues, further exploration of the abundant underused marine peptide sources is required.