Rui Liu

Background: Cardiovascular disease (CVD) is the predominant cause of mortality, with aging being a significant risk factor. Nucleotides (NTs), essential for numerous biological functions, are particularly vital under conditions like aging, starvation, and nutrient deficiency. Although the antiaging benefits of exogenous NTs have been recognized in various systems, their cardiac-specific effects are not well understood. This study, therefore, investigated the impact of exogenous NTs on cardiac aging and delved into the potential mechanisms. Methods: Senescence-accelerated mouse prone-8 (SAMP8) mice were utilized, randomly assigned to one of three groups: a control group (Control), a low-dose NTs group (NTs_L), and a high-dose NTs group (NTs_H). Meanwhile, senescence-accelerated mouse resistant 1 (SAMR1) mice were set up as the SAMR1 group. Following a 9-month intervention, cardiac tissues were subjected to analysis. Results: The results showed that NTs improved the morphological structure of the cardiac tissue, enhanced the antioxidant capacity, and mitigated inflammation. Metabolomics analysis revealed that the high-dose NT intervention improved cardiac tissue energy metabolism, potentially through activating the AMPK pathway, enhanced mitochondrial biogenesis, and increased TFAM protein expression. Conclusions: Together, these results indicate that exogenous NTs exert beneficial effects on the cardiac tissues of SAMP8 mice, potentially mitigating the cardiac aging process.

The skin, serving as the body’s primary defense against external elements, plays a crucial role in protecting the body from infections and injuries, as well as maintaining overall homeostasis. Skin aging, a common manifestation of the aging process, involves the gradual deterioration of its normal structure and repair mechanisms. Addressing the issue of skin aging is increasingly imperative. Multiple pieces of evidence indicate the potential anti-aging effects of exogenous nucleotides (NTs) through their ability to inhibit oxidative stress and inflammation. This study aims to investigate whether exogenous NTs can slow down skin aging and elucidate the underlying mechanisms. To achieve this objective, senescence-accelerated mouse prone-8 (SAMP8) mice were utilized and randomly allocated into Aging, NTs-low, NTs-middle, and NTs-high groups, while senescence-accelerated mouse resistant 1 (SAMR1) mice were employed as the control group. After 9 months of NT intervention, dorsal skin samples were collected to analyze the pathology and assess the presence and expression of substances related to the aging process. The findings indicated that a high-dose NT treatment led to a significant increase in the thickness of the epithelium and dermal layers, as well as Hyp content (p < 0.05). Additionally, it was observed that low-dose NT intervention resulted in improved aging, as evidenced by a significant decrease in p16 expression (p < 0.05). Importantly, the administration of high doses of NTs could improve, in some ways, mitochondrial function, which is known to reduce oxidative stress and promote ATP and NAD⁺ production significantly. These observed effects may be linked to NT-induced autophagy, as evidenced by the decreased expression of p62 and increased expression of LC3BI/II in the intervention groups. Furthermore, NTs were found to upregulate pAMPK and PGC-1α expression while inhibiting the phosphorylation of p38MAPK, JNK, and ERK, suggesting that autophagy may be regulated through the AMPK and MAPK pathways. Therefore, the potential induction of autophagy by NTs may offer benefits in addressing skin aging through the activation of the AMPK pathway and the inhibition of the MAPK pathway.

Extensive in vivo investigations have demonstrated the antioxidant properties of fish collagen oligopeptides (FCOPs). One of the main causes of aging and chronic non-communicable diseases is oxidative stress. Therefore, FCOPs have a broad range of applications in illness prevention and delaying aging from the standpoint of the “food is medicine” theory. However, the mechanisms that underpin the antioxidant activity of FCOPs are not completely understood. The specific objective of this essay was to investigate the antioxidant effect of FCOPs and its possible mechanism at the cellular level. Mouse embryonic fibroblasts NIH/3T3 and human vein endothelial cells (HUVECs) were exposed to 200 µM hydrogen peroxide containing different concentrations of FCOPs for 4 h and were supplemented with different concentrations of FCOPs for 24 h. Normal growth medium without FCOPs was applied for control cells. An array of assays was used to evaluate the implications of FCOPs on cellular oxidative stress status, cellular homeostasis, inflammatory levels, and mitochondrial function. We found that FCOPs exerted a protective effect by inhibiting reactive oxygen species (ROS) production, enhancing superoxide dismutase (SOD) and endothelial nitric oxide synthase (eNOS) activities and cell viability, inhibiting cell cycle arrest in the G1 phase, suppressing interleukin-1β (IL-1β), IL-6, matrix metalloproteinase-3 (MMP-3) and intercellular adhesion molecule-1(ICAM-1) secretion, downregulating nuclear factor-kappa B (NF-κB) activity, protecting mitochondrial membrane potential, and increasing ATP synthesis and NAD⁺ activities in both cells. FCOPs had a stronger antioxidant impact on NIH/3T3 than on HUVECs, simultaneously increasing glutathione peroxidase (GSH-Px) activity and decreasing malondialdehyde (MDA) content in NIH/3T3. These findings indicate that FCOPs have antioxidant effects on different tissue cells damaged by oxidative stress. FCOPs were therefore found to promote cellular homeostasis, inhibit inflammation, and protect mitochondria. Meanwhile, better health outcomes will be achieved by thoroughly investigating the effective dose and intervention time of FCOPs, as the absorption efficiency of FCOPs varies in different tissue cells.

As one of the most important barriers in the body, the intestinal barrier is a key factor in maintaining human health. Ageing of the intestine is a degenerative process that is closely associated with a variety of poor health conditions in the elderly. Inflammation and the immune system are anti-ageing targets that can regulate the function of the intestine. Nucleotides (NTs) are involved in important physiological and biochemical reactions in the body, but there are few studies about their effect on the ageing intestine. This paper examines the role of exogenous NTs in the ageing intestine. For this purpose, we used senescence-accelerated mouse prone-8 (SAMP8) mice and senescence-accelerated mouse resistant 1 (SAMR1) mice for the experiment, and randomly divided the mice into NTs-free, Normal Control, NTs-low, NTs-medium, NTs-high, and SAMR1 groups. After 9 months of intervention, we collected the colon tissue of mice for testing. In our study, exogenous NTs could increase bodyweight of mice during ageing and improve the morphological structure of the intestine, and we found that NTs could promote the secretion of intestinal protective factors, such as TFF3 and TE. Furthermore, supplementation with NTs suppressed intestinal inflammation and improved intestinal immunity, possibly by activating the p38 signaling pathway. These results suggest that exogenous NTs are able to maintain the health condition of the ageing intestine.

The study was aimed at investigating the effects of walnut oligopeptides (WOPs) on alcohol-induced acute liver injury and its underlying mechanisms. Male Sprague Dawley (SD) rats were randomly assigned to six groups: normal control, alcohol control, whey protein (440 mg/kg.bw), and three WOPs (220 mg/kg.bw, 440 mg/kg.bw, 880 mg/kg.bw) groups. After 30 days of gavage, ethanol with a volume fraction of 50%, administered at a dose of 7 g/kg.bw., caused acute liver injury. A righting reflex experiment and a blood ethanol concentration evaluation were then performed. Serum biochemical parameters, inflammatory cytokines, liver alcohol metabolism enzymes, oxidative stress biomarkers, liver nuclear factor-κB (NF-κB p65), and cytochrome P4502E1 expression were determined. The results revealed that the intervention of 440 mg/kg and 880 mg/kg WOPs could alleviate the degree of intoxication, decrease blood ethanol concentration, alleviate alcohol-induced hepatic steatosis, enhance the activity of hepatic ethanol metabolizing enzymes and antioxidant capacity, reduce lipid oxidation products and pro-inflammatory factor contents, and inhibit the expression of NF-κBp65 in the livers of rats. The outcomes of the study suggest that WOPs have beneficial effects on liver damage caused by acute ethanol binge drinking, with the high-dose WOPs (880 mg/kg.bw) exerting the most pronounced hepatoprotective effect.

Exogenous nucleotides (NTs) are considered conditionally essential nutrients, and the brain cannot synthesize NTs de novo. Therefore, the external supplementation of exogenous NTs is of great significance for maintaining normal neuronal metabolism and function under certain conditions, such as brain aging. This study, therefore, sets out to assess the neuroprotective effect of four kinds of single exogenous NTs and a mixture of the NTs, and to elucidate the potential mechanism. A rat pheochromocytoma cell line PC-12 was treated with different concentrations of exogenous NTs after 4 h of exposure to 200 µM H₂O₂. We found that the exogenous NTs exerted significant neuroprotection through decreasing neuron apoptosis and DNA damage, ameliorating inflammation and mitochondrial dysfunction, promoting cell viability, and augmenting antioxidant activity, and that they tended to up-regulate the NAD⁺/SIRTI/PGC-1α pathway involved in mitochondrial biogenesis. Among the different NTs, the neuroprotective effect of AMP seemed to be more prominent, followed by the NT mixture, NMN, and CMP. AMP also exhibited the strongest antioxidant activity in H₂O₂-treated PC-12 cells. UMP was excellent at inhibiting neuronal inflammation and improving mitochondrial function, while GMP offered major advantages in stabilizing mitochondrial membrane potential. The mixture of NTs had a slightly better performance than NMN, especially in up-modulating the NAD⁺/SIRTI/PGC-1α pathway, which regulates mitochondrial biogenesis. These results suggest that antioxidant activity, anti-inflammatory activity, and protection of mitochondrial function are possible mechanisms of the neuroprotective actions of exogenous NTs, and that the optimization of the mixture ratio and the concentration of NTs may achieve a better outcome.

Aging-related learning and memory decline are hallmarks of aging and pose a significant health burden. The effects of walnut oligopeptides (WOPs) on learning and memory were evaluated in this study. Sixty SAMP8 mice were randomly divided into four groups (15 mice/group), including one SAMP8 age-control group and three WOP-treated groups. SAMR1 mice (n = 15) that show a normal senescence rate were used as controls. The SAMP8 and SAMR1 controls were administered ordinary sterilized water, while the WOP-intervention groups were administered 110, 220, and 440 mg/kg·bw of WOPs in water, respectively. The whole intervention period was six months. The remaining 15 SAMP8 (4-month-old) mice were used as the young control group. The results showed that WOPs significantly improved the decline in aging-related learning/memory ability. WOPs significantly increased the expression of BDNF and PSD95 and decreased the level of APP and Aβ1-42 in the brain. The mechanism of action may be related to an increase in the activity of antioxidant enzymes (SOD and GSH-Px), a reduction in the expression of inflammatory factors (TNF-α and IL-1β) in the brain and a reduction in oxidative stress injury (MDA). Furthermore, the expression of AMPK, SIRT-1, and PGC-1α was upregulated and the mitochondrial DNA content was increased in brain. These results indicated that WOPs improved aging-related learning and memory impairment. WOP supplementation may be a potential and effective method for the elderly.

Brown adipose tissue (BAT) is of great importance in rodents for maintaining their core temperature via non-shivering thermogenesis in the mitochondria. BAT′s thermogenic function has been shown to decline with age. The activation of adenosine 5′-monophosphate (AMP)-activated protein kinase/sirtuin-1 (AMPK/Sirt-1) is effective in regulating mitochondrial function. Exogenous nucleotides (NTs) are regulatory factors in many biological processes. Nicotinamide mononucleotide (NMN), which is a derivative of NTs, is widely known as a Sirt-1 activator in liver and muscle, but the effect of NMN and NTs on aging BAT has not been studied before. The purpose of this study was to investigate the effect of NTs on aging senescence-accelerated mouse prone-8 (SAMP8) mice. Senescence-accelerated mouse resistant 1 (SAMR1) mice were set as the model control group and NMN was used as the positive control. Male, 3 month old SAMP8 mice were divided into the SAMP8-normal chow (SAMP8-NC), SAMP8-young-normal chow (SAMP8-young-NC), NMN, NTs-free, NTs-low, NTs-medium, and NTs-high groups for long-term feeding. After 9 months of intervention, interscapular BAT was collected for experiments. Compared to the SAMP8-NC, the body weight and BAT mass were significantly improved in the NT-treated aging SAMP8 mice. NT supplementation had effects on oxidative stress in BAT. The concentration of malondialdehyde (MDA) was reduced and that of superoxide dismutase (SOD) increased significantly. Meanwhile, the expression of the brown adipocyte markers uncoupling protein-1 (UCP-1), peroxisome proliferator-activated receptor-γ coactlvator-1α (PGC-1α), and PR domain zinc finger protein 16 (PRDM16) were upregulated. The upregulated proteins may be activated via the Sirt-1 pathway. Thus, NT supplementation may be helpful to improve the thermogenesis of BAT by reducing oxidative stress and activating the Sirt-1 pathway.

The authors would like to correct spelling mistakes (undenatured type II collagen) in the title, as well as in the main manuscript including the tables and figures in the title paper