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The Role of NAD+ in Anti-Aging Therapies

The Role of NAD+ in Anti-Aging Therapies
Xuqian Liu1 and Taosheng Huang1,2*
1Human Aging Research Institute, Nanchang University, China
2Division of Human Genetics, Cincinnati Children’s Hospital Medical Center, China
*Corresponding author: Taosheng Huang, Human Aging Research Institute, Nanchang University, Nanchang 330031 and Division of
Human Genetics, Cincinnati Children’s Hospital Medical Center, China.
To Cite This Article: Taosheng Huang, The Role of NAD+ in Anti-Aging Therapies. Am J Biomed Sci & Res. 2019 - 6(5). AJBSR.MS.ID.001072.
DOI: 10.34297/AJBSR.2019.06.001080.
Received: December 11, 2019 ; Published: December 20, 2019
Copy Right@ Taosheng Huang
This work is licensed under Creative Commons Attribution 4.0 License
American Journal of
Biomedical Science & Research
ISSN: 2642-1747
Research Article
The aging process involves accumulation of DNA damage, mitochondrial defects, progressive tissue degeneration and atrophy, and the
development of metabolic dysfunction and weakness. Aging is also accompanied by decreased levels of nicotinamide adenine dinucleotide (NAD+),
which can result in cell damage and even shorter life spans. NAD+ acts as an enzyme cofactor in many essential biological pathways and is a substrate
for several regulatory proteins. Many studies have suggested that the upregulation of NAD+ precursors can increase levels of NAD+ in tissues or cells
+. Here we provide a review of NAD+ metabolism and its role in
aging-related therapy.
Keywords: NAD+; Aging; Clinical trials
sidered to be an irreversible process. Aging of an organism is ac-
companied by metabolic disorders and the impairment of physio-
logical function, as well as the development of age-related diseases
[1-4]. There is abundant evidence that NAD+ plays an important role
in aging, as it is involved in various biological functions and is a key
regulator of stress resistance [5,6]. Levels of NAD+ steadily decline
with age, resulting in altered metabolism and increased disease
susceptibility [7-9]. NAD+ plays a key role in various energy metab-
olism pathways [6,10]. Additionally, NAD+ is a cofactor for many en-
zymes, such as poly (ADP-ribose) polymerases (PARPs), CD38, and
sirtuins [11]. Sirtuins are NAD+-dependent histone deacetylase for
a wide range of transcriptional regulators [10,12]. Overexpression
of SIRT1 in the brains of mice has been shown to delay aging [13].
PARP is a major NAD+-degrading enzyme, which plays diverse roles
in many molecular and cellular processes [14]. Inhibition of PARP-1
increases mitochondrial metabolism via modulation of SIRT1 activ-
ity [15]. Another NAD+-degrading enzyme, CD38, had been associ-
ated with the decline in NAD+ levels during aging [16].
Mammalian cells cannot import NAD+ in vivo, so they must
synthesize it either from tryptophan or the various forms of niacin
taken up in the diet including nicotinamide mononucleotide (NMN)
and nicotinamide riboside (NR) [17-20]. Recently, it was found in
mice that supplementing with NAD+ precursors (including NMN,
NR, and nicotinamide) or inhibiting the activity of NAD+-consum-
ing enzymes can increase the level of NAD+ in tissues and improve
energy metabolism, thereby delaying aging and extending healthy
life [15,21-24].
Currently, the anti-aging activity of NAD+ precursors is primar-
ily evaluated through measurement of aging markers in mouse
behavior, accumulation of DNA damage, and mitochondrial activi-
ty. RNA sequencing has also been used to identify genes and path-
ways involved in the anti-aging mechanisms of NAD+ [20,22,25,29].
Furthermore, recent research has shown that biological age can be
measured by analyzing the 353 DNA methylation sites of the Hor-
vath clock [30,31].
NAD+ Biosynthesis-Salvage Pathway
In vivo, NAD+ is an essential cofactor of dehydrogenase [32,33].
Nicotinamide coenzyme is an electron carrier which plays an im-
portant role in various oxidation-reduction reactions. Therefore
NAD+ is a cofactor of many key enzymes in glycolysis, the tricarbox-
ylic acid cycle, and oxidative phosphorylation [34]. Age-associated
American Journal of Biomedical Science & Research
Am J Biomed Sci & Res Copy@ Taosheng Huang
decline in NAD+ availability has an important effect on the aging
process of many species [8,35,36]. There are three pathways for the
synthesis of NAD+ in cells, involving many different precursors [37-
39]. Here we focus on the salvage pathway, which is important from
a translational research perspective because it is the main source
of NAD+ [40,41].
There are three pathways for the synthesis of NAD+ in cells:
a. de novo from tryptophan;
b. from nicotinic acid via the Preiss-Handler pathway; and
c. from nicotinamide (NAM) via the salvage pathway [37].
NAM itself is a by-product of NAD+-degrading enzymes such as
       -
vage pathway is catalyzed by nicotinamide phosphoribosyl-trans-
ferase (NAMPT), which converts nicotinamide and 5-phosphoribo-
syl-1-pyrophosphate into NMN [42]. Subsequently, nicotinamide
mononucleotide adenylyltransferase (NMNAT) produces NAD+
from NMN and ATP [43,44]. NR can be converted by nicotinamider-
iboside kinase (NRK) into NMN which participating in the Salvage
pathway [45]. NAMPT is the rate-limiting enzyme of the salvage
pathway [42]. It has been hypothesized that reduced NAD+ synthe-
sis is one of the causes of lower NAD+ levels with aging, and this
may be due to decreased activity of NAMPT [42,46]. Indeed, NAMPT
levels are known to decline with age in many types of tissues [47-
49], whereas exercise increases skeletal muscle NAMPT expression
Figure 1: The Salvage pathway NAM and NR are the main precursor for the salvage pathway.
In mammals, NAMPT has two different forms: intra- and ex-
tracellular [51]. The intracellular form is the one that participates
in the salvage pathway of NAD+ synthesis [42], while the extra-
cellular form likely functions as a circulating cytokine [52]. Stud-
ies have shown that secretion of NAMPT is regulated by SIRT1 in
vivo [53,54], and SIRT1 activity in turn depends on NAMPT which
regulates level of NAD+ [55]. Increasing level of NAMPT may delay
aging of individuals via SIRT1-dependent pathways [56]. NAMPT
has been shown to regulate osteoblast differentiation in primary
culture of mouse bone marrow-derived mesenchymal stem cells via
NAD+     
bone aging or fractures [48,57-59].
        
in aged mice resulted in increased levels of circulating eNAMPT, in-
creased levels of NAD+ in multiple tissues, and extended lifespan
In mammals NMNAT is the central enzyme of the NAD bio-
synthetic pathway [43,62]. There are three isoforms, NMNAT1,
NMNAT2, and NMNAT3, encoded by different genes and localized
to nucleus, Golgi apparatus, and mitochondria, respectively [43].
NMNAT1 directly control SIRT1 deacetylase activity at a set of
target gene promoters [63]. Homozygous knockout of Nmnat1 in
mice results in embryonic death [64]. Low levels of NMNAT2, high-
ly expressed in the brain and nervous system, could impair axon
regeneration as well as axon survival in aging and disease [65,66].
chondrial NAD+ biosynthesis [67]. In addition, down-regulation of
for mitochondrial respiration, suggesting that NMNAT3 plays a key
role in mitochondrial NAD+ homeostasis [68].
Anti-aging effects of NAD+
Through its role as a substrate for sirtuins, CD38, and PARP,
NAD+ regulates a variety of cellular process including energy me-
tabolism, DNA damage repair, gene expression, and oxidative stress
response [11,34,69,70].
a. The Sirtuins Pathway
Sirtuins are evolutionarily conserved NAD+-dependent deacety-
lases. Increasing sirtuin expression has been shown to affect lifes-
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American Journal of Biomedical Science & Research
pan across various species [13,36,71,72]. Sirtuins have received
 
silent information regulator 2 (Sir2) can extend yeast lifespan [72].
The closest mammalian homologue of this regulator is SIRT1[69],
mainly localized in the nucleus but also present in cytosol [73]. Its
circumstance [12]. It has been shown in vivo that NAD+-SIRT1 sig-
naling promotes mitochondrial activity [25]. Previous research has
suggested that increasing SIRT1 in the brain, especially in the dor-
somedial and lateral hypothalamic nuclei, can delay aging and ex-
sion of Sirt1 was found to delay aging and protect against oxidative
stress in the heart [74]. NR-SIRT1 signaling can inhibit cardiac stem
cell senescence by improving mitochondrial function and muscle
stem cell function, thereby enhancing life span in mice [25]. More
research is needed to determine whether increased level of NAD+ in
vivo can improve SIRT1 activity, thereby delaying aging [75].
b. The PARPs Pathway
PARPs are expressed by most eukaryotic cells and are involved
in DNA damage detection and repair, cell death pathways and so on
[14]. Aging is associated with an accumulation of DNA damage [76].
Depletion of NAD+ is involved in cell death through PARP-1 [70]. Al-
though this enzyme plays an important role in cells, over-activation
of PARP-1 can lead to depletion of NAD+, reduction of ATP, reducing
the activity of SIRT1, loss of mitochondrial function, and even cell
death [70,77,78]. Increased level of NAD+, when SIRT1 is intact, can
reduce the cell death caused by activation of PARP-1 in cardiac myo-
cyte [79].
c. CD38 and NAD+
CD38 is a multi-functional protein. Studies have shown that
CD38 is the NADase in mammalian tissues [80,81]. It is thought
to contribute to the age-related decline in NAD+ levels [23,80,82].
CD38 also acts as an antigen for B-lymphocyte activation and as an
  -
cent cells are known to express small molecules including secret-
       
process, known as the senescence-associated secretory phenotype
[84-86], involves secretion of factors by senescent cells which in-
duce the expression of CD38 in non-senescent cells [82,87]. This
and its reduced form, NADH, within a cell [82]. Recently, the small
molecule CD38 inhibitor 78c was shown to reverse the age-related
loss of NAD+ [28,83]. By increasing tissue levels of NAD+, 78c may
be able to ameliorate metabolic disorder and other disruptions in-
volved in the aging process. In addition, animals treated with 78c
show activation of longevity genes, which inhibit DNA damage [28].
NAD+ and NADH are in dynamic equilibrium within the cell
[75]. Intracellular NAD+ can be increased in vivo through oral ad-
ministration of NAD+ precursor or by inhibiting the degradation of
NAD+ [15,23,88]. Regulation of the NAD+/ NADH ratio in this way
can improve mitochondrial function and has been shown to treat
senile deafness in elderly mice [89].
NAD+ Repletion and Aging
One of the major causes of aging is progressive tissue degen-
eration and atrophy due to reduced somatic or stem cell function
[22,90,91]. Adult stem cells are not only essential in continuously
proliferating tissues (such as hematopoietic, intestinal, and skin
systems) but also in normally quiescent tissues (such as skeletal
muscle and the brain) that require regeneration after damage or
exposure to disease [92]. NR supplementation improved meta-
bolic function in muscle and neural stem cells, in both young and
old mice, thereby increasing lifespan [25]. NR treatment has also
been shown to rejuvenate stem cells from aged mice and restore
the impaired ability to repair gut damage [22]. Previous studies
have shown that DNA damage of nerve cells, nerve stem cells, and
muscle stem cells in mice can be reduced by NR supplementation
[25,93]. NR has also been shown to ameliorate mitochondrial dys-
function and enhance oxidative metabolism in obese mice [94,95]
and prolong the lifespan of mice through neuronal DNA repair and
mitochondrial quality improvement [96,97].
Supplementation with NMN can restore age-related capillary
novel therapy to restore SIRT1 activity and reverse age-related arte-
rial dysfunction by reducing oxidative stress [98,99]. Mitochondrial
disorders due to impaired oxidative phosphorylation (OXPHOS) are
a cause of aging [100]. Long-term treatment with NMN in elderly
C57BL/6J mice can improve metabolic dysfunction and ameliorate
age-associated physiological decline [20]. NMN can also restore
mitochondrial function, prevent neural death, and delay cognitive
decline in a mouse model of Alzheimer’s disease [101,102]. Sup-
plementation with NAM was shown to improve blood sugar levels
and metabolic capacity in HFD-fed mice. However, it had no effect
on lifespan [103].
There are data showing that supplementation with NAD+ pre-
cursors enhanced the mitochondrial function of cells or stem cells
in a SIRT1-dependent manner [25,94]. Furthermore, supplement-
ing NAD+ precursors in elderly mice improved mitochondrial func-
tion in hematopoietic stem cells and muscle stem cells, as well as
the biological activity of mesenchymal stromal cells through the up-
regulation of SIRT1, thereby stimulating osteogenesis of the cells
and protecting bone from aging to delay the aging of mice [105]. In
elderly mice, NMN treatment improved capillary density through
the NAD+-H2
and physiological status [27,29,106].
Inhibition of some NAD+-degrading enzymes could also lead
to increased levels of NAD+ [15,23]. CD38, PARPs, and SARM1 all
American Journal of Biomedical Science & Research
Am J Biomed Sci & Res Copy@ Taosheng Huang
degrade NAD+ inside the cell [23,77,80,107]. The activity of CD38
increases with aging, contributing to the age-related decline in
NAD+ [16]. Several small-molecule inhibitors of CD38 have been
described [83,108-110]. Thiazoloquin(az)olin(on)e is one such in-
hibitor which could potentially be used as a therapeutic agent to in-
crease intracellular NAD+ level [28]. Inhibition of PARP1 has recent-
ly been reported to correct mitochondrial impairment [111,112]
and has strong metabolic implications through its modulation of
SIRT1 activity [15].
Measure Biological Age
Thus far, the anti-aging activity of NAD+ is mainly examined us-
ing RNA sequencing and gene set enrichment analysis to identify
pathways of candidate biomarkers [20,22,25]. However, there is
not yet a gold standard for aging biomarkers. The DNA clock may
offer a better objective biomarker for the study of aging [30,31].
DNA methylation plays a critical role in the regulation of gene tran-
scription [113-118]. Senescence can be predicted and evaluated by
detecting cytosine-5 methylation within CpG dinucleotides [30,31].
These age-related CpG characteristics are independent of gender or
tissue type. Recent research has shown that biological age can be
approximated by measuring levels of DNA methylation, a process
known as the Horvath (or DNA) clock [30,31,119,120]. Age-related
   -
parison of thousands of CpG sites in Illumina Bead Chip microarray
data [121,122]. Many of these age-associated CpG sites were then
used as epigenetic age-predictors [30,31,120,123]. Three hun-
    
of biological age, independent of chromatin status or tissue source
Petkovich et al. developed a robust predictor of mouse biologi-
cal age based on 90 CpG sites derived from partial blood DNA meth-
      -
sue predictor to estimate age based on DNA methylation at 329
unique CpG sites from various different mouse tissues [125]. One
group claims to have found three methylation sites, Prima1, Hsf4,
and Kcns1, which are enough to predict biological age in mice [126].
However, this study has yet to be replicated. The most accurate
clock results from applying elastic net regression to all CpGs for
multi-tissue in mice [127].
Together these studies suggest that the DNA clock provides an
objective biomarker for the study of aging [30,31]. Recently, met-
formin has shown that reversed subject’s biological age, based on
assessment of Horvath clock [128,129]. Its use will allow us to ex-
amine the anti-aging effectiveness of NAD+ and its precursors more
objectively and accurately.
Clinical Research
NAD+ precursors can be delivered orally to humans or ani-
mals to alter the dynamic balance of NAD+/NADH in vivo [24,130].
Preliminary clinical studies in humans showed that NR supple-
mentation could improve muscle NAD+ metabolism in the elderly
[131,132]. Healthy volunteers, who underwent an 8-day course
of NR, with doses increasing from 250 mg to 1000 mg, showed
increased levels of circulating NAD+ and experienced no adverse
side effects [133]. Similarly, NR supplementation increased NADH
and NADPH levels and improved exercise performance in elderly
subjects [134]. Therefore, NMN is considered safe in clinical trials
[135]. However, high dose supplementation with NAD+ precursors
may increase rates of glycolysis and mitochondrial respiratory me-
 -
tokines in cells [136]. Thus, use of supplements should be carefully
observed to ensure that they strike a proper balance between an-
ti-aging effects and potential detrimental effects.
NAD+ is a cofactor for many important enzymes. Reduced
levels of NAD+ have been associated with aging. Evidence suggests
that supplementation with NAD+ precursors, or inhibition of
NAD+ degradation, could improve metabolic function. While
supplementation with NAD+ precursors has been found to delay
aging in mice, anti-aging effects of NAD+ have yet to be demonstrated
in human subjects. Use of a more accurate biomarker for aging,
     
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Nicotinamide adenine dinucleotide (NAD+) is modulated by conditions of metabolic stress and has been reported to decline with aging in preclinical models, but human data are sparse. Nicotinamide riboside (NR) supplementation ameliorates metabolic dysfunction in rodents. We aimed to establish whether oral NR supplementation in aged participants can increase the skeletal muscle NAD+ metabolome and if it can alter muscle mitochondrial bioenergetics. We supplemented 12 aged men with 1 g NR per day for 21 days in a placebo-controlled, randomized, double-blind, crossover trial. Targeted metabolomics showed that NR elevated the muscle NAD+ metabolome, evident by increased nicotinic acid adenine dinucleotide and nicotinamide clearance products. Muscle RNA sequencing revealed NR-mediated downregulation of energy metabolism and mitochondria pathways, without altering mitochondrial bioenergetics. NR also depressed levels of circulating inflammatory cytokines. Our data establish that oral NR is available to aged human muscle and identify anti-inflammatory effects of NR.
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Age-related hearing loss (ARHL) is a major neurodegenerative disorder and the leading cause of communication deficit in the elderly population, which remains largely untreated. The development of ARHL is a multifactorial event that includes both intrinsic and extrinsic factors. Recent studies suggest that NAD+ /NADH ratio may play a critical role in cellular senescence by regulating sirtuins, PARP-1, and PGC-1α. Nonetheless, the beneficial effect of direct modulation of cellular NAD+ levels on aging and age-related diseases has not been studied, and the underlying mechanisms remain obscure. Herein, we investigated the effect of β-lapachone (β-lap), a known plant-derived metabolite that modulates cellular NAD+ by conversion of NADH to NAD+ via the enzymatic action of NADH: quinone oxidoreductase 1 (NQO1) on ARHL in C57BL/6 mice. We elucidated that the reduction of cellular NAD+ during the aging process was an important contributor for ARHL; it facilitated oxidative stress and pro-inflammatory responses in the cochlear tissue through regulating sirtuins that alter various signaling pathways, such as NF-κB, p53, and IDH2. However, augmentation of NAD+ by β-lap effectively prevented ARHL and accompanying deleterious effects through reducing inflammation and oxidative stress, sustaining mitochondrial function, and promoting mitochondrial biogenesis in rodents. These results suggest that direct regulation of cellular NAD+ levels by pharmacological agents may be a tangible therapeutic option for treating various age-related diseases, including ARHL.
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Mesenchymal stromal cells (MSCs) can differentiate to various cell types including osteoblasts, chondrocytes, and adipocytes. This cellular flexibility contributes to widespread clinical use of MSCs in tissue repair. However, challenges remain in efficient cellular expansion of MSCs for stem cell therapy. Current MSC culture methods have resulted in reduced self-renewal of MSCs and compromised therapeutic outcomes. This study identifies that nicotinamide mononucleotide (NMN), a key natural NAD+ intermediate, effectively encourages MSC expansion in vitro and in vivo. The in vitro expanded MSCs had heightened osteogenesis, but reduced adipogenesis. Furthermore, NMN supplementation stimulated osteogenesis of endogenous MSCs, and protected bone from aging and irradiation induced damage in mice. Mechanistically, we found that NMN treatment upregulated SIRT1. Genetically overexpressing SIRT1 in MSCs by using Prx1 cre; ColA1flox-stop-flox-SIRT1 mice promoted osteogenesis and reduced adipogenesis in aged mice. Overall, our data demonstrate that NMN promoted MSC self-renewal with strengthened osteogenesis and reduced adipogenesis via upregulating SIRT1 in aged mice.
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Tissue nicotinamide adenine dinucleotide (NAD ⁺ ) decline has been implicated in aging. We have recently identified CD38 as a central regulator involved in tissue NAD ⁺ decline during the aging process. CD38 is an ecto-enzyme highly expressed in endothelial and inflammatory cells. To date, the mechanisms that regulate CD38 expression in aging tissues characterized by the presence of senescent cells is not completely understood. Cellular senescence has been described as a hallmark of the aging process and these cells are known to secrete several factors including cytokines and chemokines through their senescent associated secretory phenotype (SASP). Here we investigated if the cellular senescence phenotype is involved in the regulation of CD38 expression and its NADase activity. We observed that senescent cells do not have high expression of CD38. However, the SASP factors secreted by senescent cells induced CD38 mRNA and protein expression and increased CD38-NADase activity in non-senescent cells such as endothelial cells or bone marrow derived macrophages. Our data suggest a link between cellular senescence and NAD ⁺ decline in which SASP-mediated upregulation of CD38 can disrupt cellular NAD ⁺ homeostasis.
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Cellular senescence is a stable growth arrest that is implicated in tissue ageing and cancer. Senescent cells are characterized by an upregulation of proinflammatory cytokines, which is termed the senescence-associated secretory phenotype (SASP). NAD+ metabolism influences both tissue ageing and cancer. However, the role of NAD+ metabolism in regulating the SASP is poorly understood. Here, we show that nicotinamide phosphoribosyltransferase (NAMPT), the rate-limiting enzyme of the NAD+ salvage pathway, governs the proinflammatory SASP independent of senescence-associated growth arrest. NAMPT expression is regulated by high mobility group A (HMGA) proteins during senescence. The HMGA–NAMPT–NAD+ signalling axis promotes the proinflammatory SASP by enhancing glycolysis and mitochondrial respiration. HMGA proteins and NAMPT promote the proinflammatory SASP through NAD+-mediated suppression of AMPK kinase, which suppresses the p53-mediated inhibition of p38 MAPK to enhance NF-κB activity. We conclude that NAD+ metabolism governs the proinflammatory SASP. Given the tumour-promoting effects of the proinflammatory SASP, our results suggest that anti-ageing dietary NAD+ augmentation should be administered with precision. Nacarelli et al. show that the nicotinamide-phosphoribosyltransferase-regulated NAD+ biogenesis pathway promotes the proinflammatory senescence-associated secretory phenotype by enhancing glycolysis and mitochondrial respiration during senescence.
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Purpose Older individuals suffer from low NADH levels. We have previously shown that nicotinamide riboside [NR; a NAD(P)(H) precursor] administration impaired exercise performance in young rats. It has been suggested that supplementation of redox agents exerts ergogenic effect only in deficient individuals. We hypothesized that old individuals would more likely benefit from NR supplementation. We investigated the effect of acute NR supplementation on redox homeostasis and physical performance in young and old individuals. Methods Twelve young and twelve old men received NR or placebo in a double-blind cross-over design. Before and 2 h after NR or placebo supplementation, blood and urine samples were collected, while physical performance (VO2max, muscle strength, and fatigue) was assessed after the second blood sample collection. Results At rest, old individuals exhibited lower erythrocyte NAD(P)H levels, higher urine F2-isoprostanes and lower erythrocyte glutathione levels compared to young (P < 0.05). NR supplementation increased NADH (51% young; 59% old) and NADPH (32% young; 38% old) levels in both groups (P < 0.05), decreased F2-isoprostanes by 18% (P < 0.05), and tended to increase glutathione (P = 0.078) only in the old. NR supplementation did not affect VO2max and concentric peak torque, but improved isometric peak torque by 8% (P = 0.048) and the fatigue index by 15% (P = 0.012) in the old. In contrast, NR supplementation did not exert any redox or physiological effect in the young. Conclusions NR supplementation increased NAD(P)H levels, decreased oxidative stress, and improved physical performance only in old subjects, substantiating that redox supplementation may be beneficial only in individuals with antioxidant deficiencies.
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ELife digest Epigenetic marks are chemical modifications found throughout the genome – the DNA within cells. By influencing the activity of nearby genes, the marks govern developmental processes and help cells to adapt to changes in their surroundings. Some epigenetic marks can be gained or lost with age. A lot of aging research focuses on one type of mark, called “DNA methylation”. By measuring the presence or absence of specific methyl groups, scientists can estimate biological age – which may differ from calendar age. Recent studies have developed computer models called epigenetic aging clocks to predict the biological age of mouse cells. These clocks use epigenetic data collected from the entire genomes of mice, and are useful for understanding how the aging process is affected by genetic parameters, diet, or other environmental factors. Yet, the genome sequencing methods used to construct most existing epigenetic clocks are expensive, labor-intensive, and cannot be easily applied to large groups of mice. Han et al. have developed a new way to predict biological aging in mice that needs methylation information from just three particular sections of the genome. Even though this approach is much faster and less expensive than other epigenetic approaches to measuring aging, it has a similar level of accuracy to existing models. Han et al. use the new method to show that cells from different strains of laboratory mice age at different rates. Furthermore, in a strain that has a shorter life expectancy, aging seems to be accelerated. The new approach developed by Han et al. will make it easier to study how aging in mice is affected by different interventions. Further studies will also be needed to better understand how epigenetic marks relate to biological aging.
In a small trial, drugs seemed to rejuvenate the body’s ‘epigenetic clock’, which tracks a person’s biological age. In a small trial, a cocktail of drugs seemed to rejuvenate the body’s ‘epigenetic clock’. Man participating in the 5k race during the Rock n Roll Virginia Beach Half Marathon, Virginia
Aging is a significant risk factor for impaired tissue functions and chronic diseases. Age-associated decline in systemic NAD+ availability plays a critical role in regulating the aging process across many species. Here, we show that the circulating levels of extracellular nicotinamide phosphoribosyltransferase (eNAMPT) significantly decline with age in mice and humans. Increasing circulating eNAMPT levels in aged mice by adipose-tissue-specific overexpression of NAMPT increases NAD+ levels in multiple tissues, thereby enhancing their functions and extending healthspan in female mice. Interestingly, eNAMPT is carried in extracellular vesicles (EVs) through systemic circulation in mice and humans. EV-contained eNAMPT is internalized into cells and enhances NAD+ biosynthesis. Supplementing eNAMPT-containing EVs isolated from young mice significantly improves wheel-running activity and extends lifespan in aged mice. Our findings have revealed a novel EV-mediated delivery mechanism for eNAMPT, which promotes systemic NAD+ biosynthesis and counteracts aging, suggesting a potential avenue for anti-aging intervention in humans.
Human DNA-methylation data have been used to develop highly accurate biomarkers of aging ("epigenetic clocks"). Recent studies demonstrate that similar epigenetic clocks for mice (Mus Musculus) can be slowed by gold standard anti-aging interventions such as calorie restriction and growth hormone receptor knock-outs. Using DNA methylation data from previous publications with data collected in house for a total 1189 samples spanning 193,651 CpG sites, we developed 4 novel epigenetic clocks by choosing different regression models (elastic net- versus ridge regression) and by considering different sets of CpGs (all CpGs vs highly conserved CpGs). We demonstrate that accurate age estimators can be built on the basis of highly conserved CpGs. However, the most accurate clock results from applying elastic net regression to all CpGs. While the anti-aging effect of calorie restriction could be detected with all types of epigenetic clocks, only ridge regression based clocks replicated the finding of slow epigenetic aging effects in dwarf mice. Overall, this study demonstrates that there are trade-offs when it comes to epigenetic clocks in mice. Highly accurate clocks might not be optimal for detecting the beneficial effects of anti-aging interventions.