NAD+ and Aging
NAD+ and AGING
As we age NAD (NAD+ and NADH) significantly declines, further driving the aging process.
NAD+ declining with age: 
WHY DOES NAD+ DECREASE?
NAD depletion may play a major role in the aging process as it limits:
- DNA repair
- Energy production
- Genomic signalling 
NAD+ AND LONGEVITY
One way NAD+ seems to exert its health-promoting properties is by helping sirtuins do their job.
Sirtuins are proteins that regulate biological pathways and help protect cells from age-related decline.
NAD+ increases the activity of:
SIRT1 induces formation of new mitochondria
SIRT6 maintains length of telomeres (the end caps on DNA) ASSOCIATED WITH LONGEVITY. 
Beneficial effects of increased NAD+ levels and sirtuin activation on mitochondrial homeostasis, metabolism and longevity have been established across species. 
NAD - A THERAPEUTIC TARGET
Recent studies implicate NAD+ biosynthesis as a
POTENTIAL TARGET FOR AGE-ASSOCIATED ISSUES.
Studies have demonstrated the therapeutic potential of supplementing NAD + intermediates.
This provides a proof of concept for the development of an EFFECTIVE ANTI-AGING INTERVENTION.
NAD+ intermediates include NMN (nicotinamide mononucleotide) and NR (nicotinamide riboside). 
The upregulation of NAD metabolism, including dietary supplementation with NAD precursors, has been shown to prevent the decline of NAD.
Upregulation of NAD has BENEFICIAL EFFECTS AGAINST AGING.
All supporting the fact that NAD metabolism plays important roles in aging and longevity. 
NR SUPPLEMENTATION IN MICE
Aging triggers NAD+ loss in old mice, by activating PARPS.
A reduction in NAD+ lowers activity of the anti-aging proteins sirtuins.
Supplementing mice with NR restores NAD+ reversing the cycle.
RESULTING IN BETTER STEM CELL MAINTENANCE AND TISSUE FUNCTION. 
NAD DEPENDANT ENZYMES MEDIATING AGE
CD38, Sirtuins, PARPs and SARM1: 
Sirtuins are evolutionary conserved regulators for aging and longevity in organisms.
Each sirtuin has different functions and is localized to different subcellular compartments.
Is localized to the nucleus but is also present in the cytosol.
Is present in the cytosol but can also be present in the nucleus.
Are localized in the mitochondria.
Is localized in the nucleus.
Is localized in the nucleolus.
Sirtuins are classified as class III histone deacetylases dependent on NAD+.
Sirtuins have other enzymatic activities:
- SIRT4 - demethylglutarylase and other lysine deacylase activities
- SIRT5 - demalonylase and desuccinylase activities
- SIRT6 - de-long chain fatty deacylase activity
- SIRT4/6 - ADP-ribosyltransferase activity
These various NAD+ dependent functions mean they are key regulators of aging and longevity.
It has been demonstrated that SIRT1 overexpression in the brain Delayed Aging & Extended Life Span. 
Systemic overexpression of SIRT6 in male mice also showed life span extension. 
PARP is a protein found in our cells and stands for poly-ADP ribose polymerase.
PARPs also use NAD+ and cleave it into nicotinamide and ADP-ribose (ADPR), producing a chain of ADPR.
PARP1 and 2 respond to DNA strand breaks and facilitate DNA repair in the nucleus.
NAD+ is a common substrate between PARPs & SIRT1 - there is competition between their activities.
Deletion increases NAD+ levels.
Deletion increases SIRT1 expression. This enhances the activity of SIRT1.
Increasing activity of SIRT1: 
Protects us from diet-induced obesity
Increases mitochondrial activity
Increases fatty acid oxidation
PARP during DNA repair: 
As we age, PARP activation contributes to a decrease in intracellular NAD+.
This causes a decrease in SIRT1 activity. 
DNA DAMAGE RESPONSE – SIRT1 & PARP
Relationship between SIRT1 & PARP in double-strand break induced (DSB) DNA damage response. 
DNA double-strand break activates PARP
This leads to the depletion of NAD+ and inactivation of SIRT1 deacetylase activity.
SARM1 (Sterile Alpha and toll / interleukin-1 Receptor Motif containing 1) is another NAD+ hydrolase.
SARM1 is essential in neurodegeneration.
An axon is a nerve fibre that conducts electrical impulses around our body.
Axonal injury is accompanied by a depletion of NAD+.
Loss of SARM1 function delays axonal degeneration.
Studies show that the TIR domain of SARM1 is responsible for the NAD+ activity, promoting axonal degeneration. 
This has identified a target treatment of neurodegenerative diseases.
MECHANISM OF ACTION
CD38 is a membrane-bound NADase – it hydrolyses NAD+ to nicotinamide and ADP-ribose.
As we age, its protein levels increase, increasing NADase activity and declining NAD+ levels.
Studies have shown CD38 deficient mice are protected from mitochondrial dysfunction and diabetes during aging. 
Cyclic ADP ribose hydrolase (CD38) protein, chemical structure:
THE RELATIONSHIP BETWEEN NAD AND CD38
NAD decreases during aging via CD38
Inhibiting CD38 prevents NAD decline, leading to sirtuin activation & protection against age-related diseases 
As discussed, CD38 modulates NAD+ levels as observed in this study.
The activity of CD38 generates ADPR and nicotinamide by hydrolysis of NAD+.
It also mediates cellular signalling through the generation of cyclic ADPR (cADPR).
There has been in depth research into the NADase activity of CD38. 
CD38 can degrade the NAD+ precursors, NMN and NR, modulating NAD+ content within a cell.
CD38 protein levels increase in multiple tissues and organs as we age.
This contributes to NAD+ decline and Metabolic Syndrome. 
Inhibiting CD38 leads to an increase in NAD+ levels and can improve glucose and lipid metabolism. 
Two CD38 inhibitors were used to treat Metabolic Syndrome: Quercetin & Apigenin.
INFLAMMATION AND CD38
CD38 expression is induced by inflammation.
Age-related chronic inflammation may increase CD38 causing a decline in NAD+.
Senescent cells (cells which have stopped dividing) accumulate during aging.
These cells secrete CD38 as part of the pro-inflammatory response called the senescence-associated secretory phenotype (SASP). 
NAD PLAYS A VITAL ROLE IN THE AGING PROCESS
NAD boosting therapies, such as supplementation with NAD+, NMN and NR, represent a prospect for true rejuvenation therapy.
NAD PRECURSORS PROTECT AGAINST AGING-ASSOCIATED DISEASES
Boosting NAD metabolism can act as anti-aging in humans.