James Clement

The view of aging has evolved in parallel with the advances in biomedical sciences. Long considered as an irreversible process where interventions were only aimed at slowing down its progression, breakthrough discoveries like animal cloning and cell reprogramming have deeply changed our understanding of postnatal development, giving rise to the emerging view that the epigenome is the driver of aging. The idea was significantly strengthened by the converging discovery that DNA methylation (DNAm)… Show more

The view of aging has evolved in parallel with the advances in biomedical sciences. Long considered as an irreversible process where interventions were only aimed at slowing down its progression, breakthrough discoveries like animal cloning and cell reprogramming have deeply changed our understanding of postnatal development, giving rise to the emerging view that the epigenome is the driver of aging. The idea was significantly strengthened by the converging discovery that DNA methylation (DNAm) at specific CpG sites could be used as a highly accurate biomarker of age defined by an algorithm known as the Horvath clock. It was at this point where epigenetic rejuvenation came into play as a strategy to reveal to what extent biological age can be set back by making the clock tick backwards. Initial evidence suggests that when the clock is forced to tick backwards in vivo, it is only able to drag the phenotype to a partially rejuvenated condition. In order to explain the results, a bimodular epigenome is proposed, where module A represents the DNAm clock component and module B the remainder of the epigenome. Epigenetic rejuvenation seems to hold the key to arresting or even reversing organismal aging. Show less

Highlights:
• Nicotinamide adenine dinucleotide (NAD+) is an important target to extend lifespan and health span.
• Age-related accumulation of oxidative stress can deplete NAD+.
• NAD+ precursors, exercise and caloric restriction can increase NAD+ levels.
• NAD+ is also an important factor in tumor biology and some infections and immunological roles.
• Accurately quantifying NAD+ represents an unexplored yet important component of NAD+ therapy.

Nicotinamide adenine dinucleotide (NAD+) is an essential pyridine nucleotide that serves as an electron carrier in cellular metabolism and plays a crucial role in the maintenance of balanced redox homeostasis. Quantification of NAD+:NADH and NADP+:NADPH ratios are pivotal to a wide variety of cellular processes, including intracellular secondary messenger signaling by CD38 glycohydrolases, DNA repair by poly(adenosine diphosphate ribose) polymerase (PARP), epigenetic regulation of gene… Show more

Nicotinamide adenine dinucleotide (NAD+) is an essential pyridine nucleotide that serves as an electron carrier in cellular metabolism and plays a crucial role in the maintenance of balanced redox homeostasis. Quantification of NAD+:NADH and NADP+:NADPH ratios are pivotal to a wide variety of cellular processes, including intracellular secondary messenger signaling by CD38 glycohydrolases, DNA repair by poly(adenosine diphosphate ribose) polymerase (PARP), epigenetic regulation of gene expression by NAD-dependent histone deacetylase enzymes known as sirtuins, and regulation of the oxidative pentose phosphate pathway. We quantified changes in the NAD+ metabolome in plasma samples collected from consenting healthy human subjects across a wide age range (20-87 years) using liquid chromatography coupled to tandem mass spectrometry. Our data show a significant decline in the plasma levels of NAD+, NADP+, and other important metabolites such as nicotinic acid adenine dinucleotide (NAAD) with age. However, an age-related increase in the reduced form of NAD+ and NADP+-NADH and NADPH-and nicotinamide (NAM), N-methyl-nicotinamide (MeNAM), and the products of adenosine diphosphoribosylation, including adenosine diphosphate ribose (ADPR) was also reported. Whereas, plasma levels of nicotinic acid (NA), nicotinamide mononucleotide (NMN), and nicotinic acid mononucleotide (NAMN) showed no statistically significant changes across age groups. Taken together, our data cumulatively suggest that age-related impairments are associated with corresponding alterations in the extracellular plasma NAD+ metabolome. Our future research will seek to elucidate the role of modulating NAD+ metabolites in the treatment and prevention of age-related diseases. Show less

Nicotinamide adenine dinucleotide (NAD+) is an essential cofactor and substrate for several critical cellular processes involved in ATP production, DNA repair, epigenetically modulated gene expression, intracellular calcium signalling and immunological functions. NAD+ depletion may occur in response to either excessive DNA damage due to free radical or UV attack, resulting in significant PARP activation and a high turnover and subsequent depletion of NAD+, chronic immune activation and… Show more

Nicotinamide adenine dinucleotide (NAD+) is an essential cofactor and substrate for several critical cellular processes involved in ATP production, DNA repair, epigenetically modulated gene expression, intracellular calcium signalling and immunological functions. NAD+ depletion may occur in response to either excessive DNA damage due to free radical or UV attack, resulting in significant PARP activation and a high turnover and subsequent depletion of NAD+, chronic immune activation and inflammatory cytokine production resulting in accelerated CD38 activity and decline in NAD+ levels. Recent studies have shown that enhancing NAD+ levels can profoundly reduce oxidative cell damage in catabolic tissue, including the brain. Therefore, promotion of intracellular NAD+ anabolism represents a promising therapeutic strategy for age-associated degenerative diseases in general, and is essential to the effective realisation of multiple benefits of healthy sirtuin activity. Herein, we discuss recent insights regarding the efficacy and benefits of the NAD+ precursors, nicotinamide (NAM), nicotinic acid (NA), nicotinamide riboside (NR), and nicotinamide mononucleotide (NMN) in attenuating NAD+ decline in degenerative disease states and physiological ageing. While NAD+ precursors can play important protective roles in several diseases, these precursors may vary in their ability to enhance NAD+ synthesis via their location in the NAD+ anabolic pathway. The refinement of personalised therapy for the use of NAD+ precursors, and improved detection methodologies allowing the administration of specific NAD+ precursors in the context of patients' NAD+ levels will lead to a better understanding of the therapeutic role of NAD+ precursors in human diseases. Show less

Present knowledge of its central nervous system makes the cat a desirable subject for studies of brain-behavior relationships. Response frequencies and latency characteristics in conditioning and control groups indicate that the response of the nictitating membrane can be classically conditioned in a new restraint system in which detailed brain and behavior measures can be easily obtained.