Sirtuins at the Service of Healthy Longevity

Abstract

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.

Keywords: anti-aging mechanisms; anti-inflammatory action; caloric restriction; metabolic austerity; neurodegeneration prevention; protective effects; sirtuins.

FIGURE 1

Life span-extending effects of caloric restriction – the key role of sirtuins. ^∗ increased availability of NAD+ can activate all sirtuins, while increased AMP concentration can activate all sirtuins except SIRT4. AMP – adenosine monophosphate, AMPK – AMP-activated protein kinase, ATP – adenosine triphosphate, CSP – cell senescence phenotype, FFA – free fatty acids, FoxOs – forkhead box proteins, mTOR – mammalian target of rapamycin kinase (a protein), NAD+ – nicotinamide adenine dinucleotide, NADH – nicotinamide adenine dinucleotide hydride (reduced NAD+), NRF-1 – nuclear respiratory factor 1 (a transcription factor), ROS – reactive oxygen species, TCA cycle – tricarboxylic acid cycle.

FIGURE 2

Enzymatic activities within the sirtuin family members (Table) and epigenetic DNA modifications resulting in the proven protective effects throughout the human body (see the main text for details). ^∗ Unlike other sirtuins, SIRT2 may exert pro-inflammatory actions in the kidneys and pro- inflammatory and pro-fibrotic effects in the liver.