Sirtuins may counteract at least six hallmarks of organismal aging: neurodegeneration, chronic but ineffective inflammatory response, metabolic syndrome, DNA damage, genome instability, and cancer incidence. Moreover, caloric restriction is believed to slow down aging by boosting the activity of some sirtuins through activating adenosine monophosphate-activated protein kinase (AMPK), thus raising the level of intracellular nicotinamide adenine dinucleotide (NAD⁺) by stimulating NAD⁺ biosynthesis. Sirtuins and their downstream effectors induce intracellular signaling pathways related to a moderate caloric restriction within cells, mitigating reactive oxygen species (ROS) production, cell senescence phenotype (CSP) induction, and apoptosis as forms of the cellular stress response. Instead, it can promote DNA damage repair and survival of cells with normal, completely functional phenotypes. In this review, we discuss mechanisms of sirtuins action toward cell-conserving phenotype associated with intracellular signaling pathways related to moderate caloric restriction, as well as some tissue-specific functions of sirtuins, especially in the central nervous system, heart muscle, skeletal muscles, liver, kidneys, white adipose tissue, hematopoietic system, and immune system. In this context, we discuss the possibility of new therapeutic approaches.

Diabetes mellitus is one of the most common metabolic diseases worldwide, and its long-term complications include neuropathy, referring both to the peripheral and to the central nervous system. Detrimental effects of dysglycemia, especially hyperglycemia, on the structure and function of the blood–brain barrier (BBB), seem to be a significant backgrounds of diabetic neuropathy pertaining to the central nervous system (CNS). Effects of hyperglycemia, including excessive glucose influx to insulin-independent cells, may induce oxidative stress and secondary innate immunity dependent inflammatory response, which can damage cells within the CNS, thus promoting neurodegeneration and dementia. Advanced glycation end products (AGE) may exert similar, pro-inflammatory effects through activating receptors for advanced glycation end products (RAGE), as well as some pattern-recognition receptors (PRR). Moreover, long-term hyperglycemia can promote brain insulin resistance, which may in turn promote Aβ aggregate accumulation and tau hyperphosphorylation. This review is focused on a detailed analysis of the effects mentioned above towards the CNS, with special regard to mechanisms taking part in the pathogenesis of central long-term complications of diabetes mellitus initiated by the loss of BBB integrity.

Vascular endothelial growth factor (VEGF) and placenta growth factor (PlGF) cause vasodilation. We examined the vasomotor response of isolated placental vessels to VEGF and PlGF in normal (group I) and intrauterine growth retardation (IUGR)-complicated pregnancy (group II). Rings of vessels were prepared in vitro and mounted on the vessel myograph plunged in tissue bath. The magnitude of dilation to increased doses of VEGF and PlGF has been studied. VEGF is a more potent vasodilator than PlGF. Both, VEGF- and PlGF-induced vasorelaxation was diminished in the IUGR (group II) nearly by half, compared to control (group I). Relative placental nitric oxide deficiency, or decreased sensitivity to VEGF and PlGF may contribute to the development of high impedance fetoplacental circulation.

Both basic pathomechanisms underlying Alzheimer’s disease and some premises for stipulating a possible preventive role of some sirtuins, especially SIRT1 and SIRT3, protective against Alzheimer’s disease-related pathology, are discussed in this article. Sirtuins can inhibit some processes that underlie Alzheimer’s disease-related molecular pathology (e.g., neuroinflammation, neuroinflammation-related oxidative stress, Aβ aggregate deposition, and neurofibrillary tangle formation), thus preventing many of those pathologic alterations at relatively early stages of their development. Subsequently, the authors discuss in details which mechanisms of sirtuin action may prevent the development of Alzheimer’s disease, thus promoting brain homeostasis in the course of aging. In addition, a rationale for boosting sirtuin activity, both with allosteric activators and with NAD⁺ precursors, has been presented.