RESUMEN
Advanced paternal age has increasingly been recognized as a risk factor for male fertility and progeny health. While underlying causes are not well understood, aging is associated with a continuous decline of blood and tissue NAD+ levels, as well as a decline of testicular functions. The important basic question to what extent ageing-related NAD+ decline is functionally linked to decreased male fertility has been difficult to address due to the pleiotropic effects of aging, and the lack of a suitable animal model in which NAD+ levels can be lowered experimentally in chronologically young adult males. We therefore developed a transgenic mouse model of acquired niacin dependency (ANDY), in which NAD+ levels can be experimentally lowered using a niacin-deficient, chemically defined diet. Using ANDY mice, this report demonstrates for the first time that decreasing body-wide NAD+ levels in young adult mice, including in the testes, to levels that match or exceed the natural NAD+ decline observed in old mice, results in the disruption of spermatogenesis with small testis sizes and reduced sperm counts. ANDY mice are dependent on dietary vitamin B3 (niacin) for NAD+ synthesis, similar to humans. NAD+-deficiency the animals develop on a niacin-free diet is reversed by niacin supplementation. Providing niacin to NAD+-depleted ANDY mice fully rescued spermatogenesis and restored normal testis weight in the animals. The results suggest that NAD+ is important for proper spermatogenesis and that its declining levels during aging are functionally linked to declining spermatogenesis and male fertility. Functions of NAD+ in retinoic acid synthesis, which is an essential testicular signaling pathway regulating spermatogonial proliferation and differentiation, may offer a plausible mechanism for the hypospermatogenesis observed in NAD+-deficient mice.
Asunto(s)
Niacina , Envejecimiento , Animales , Masculino , Ratones , Ratones Transgénicos , NAD/metabolismo , NAD/farmacología , Niacina/metabolismo , Niacina/farmacología , EspermatogénesisRESUMEN
In mammals, nicotinamide (NAM) is the primary NAD precursor available in circulation, a signaling molecule, and a precursor for methyl-nicotinamide (M-NAM) synthesis. However, our knowledge about how the body regulates tissue NAM levels is still limited. Here we demonstrate that dietary vitamin B3 partially regulates plasma NAM and NAM-derived metabolites, but not their tissue levels. We found that NAD de novo synthesis from tryptophan contributes to plasma and tissue NAM, likely by providing substrates for NAD-degrading enzymes. We also demonstrate that tissue NAM is mainly generated by endogenous metabolism and that the NADase CD38 is the main enzyme that produces tissue NAM. Tissue-specific CD38-floxed mice revealed that CD38 activity on endothelial and immune cells is the major contributor to tissue steady-state levels of NAM in tissues like spleen and heart. Our findings uncover the presence of different pools of NAM in the body and a central role for CD38 in regulating tissue NAM levels.
RESUMEN
UNLABELLED: OBJECTIVE AND SCOPE: To validate a protocol for the detection of malnutrition risk in a population of elderly patients admitted to a general hospital for non-surgical reasons. MATERIALS AND METHOD: The study involved 95 patients (34 of them male) over the age of 65 who were assessed on the third and fifth day after admission by means of a simple screening protocol (PC in its Spanish acronym) that considered recent changes in weight, serum albumin, lymphocyte concentration, food intake and diagnosis on admission, together with a more complex diagnostic protocol (PD in its Spanish acronym) including anthropometric, biochemical and immunological parameters. The PC was applied by personnel not expert in nutrition, while the PD was carried out by persons trained in nutritional assessment. The results of the PC and PD were compared, with statistical significance being considered at levels of p < 0.05. RESULTS: According to the PD, 75 patients (78.9%) suffered protein-energy malnutrition (39 slight, 31 moderate, 5 severe). The score obtained in the PC had a significant relationship with the severity of the malnutrition diagnosed using PD (p < 0.001). Furthermore, the absence or presence of nutritional risk assessed using the PC had a significant correlation with the diagnosis of malnutrition and its degree according to the PD (p < 0.01), thus indicating the validity of the PC as a method for screening of malnutrition. CONCLUSIONS: 1. In our population of geriatric patients admitted for reasons other than surgery, there was a high prevalence of protein-energy malnutrition. 2. The risk of malnutrition in an elderly population in hospital settings is appropriately assessed by means of a simple screening test effected by non-specialized personnel. 3. The score obtained in the PC is linked with the presence of malnutrition and with its severity. 4. The use of simple screening techniques in populations with a high prevalence of malnutrition may contribute to the detection and correction of this problem.