The NAD+ Stack

A deep-dive into Renue by Science and the NAD+ stack I've been using since 2024

The Michelle Edit | Michelle Saram

There is a version of this essay that begins with the supplements. The ingredients, the mechanisms, the peer-reviewed citations stacked like evidence at a trial. I have spent considerable time going into the research.

But I want to begin somewhere else.

Does your body know how to receive this?

Is the ingredient pure? Does the mechanism make biological sense? Is the internal environment — the drainage, the detoxification, the cellular membrane integrity, the mitochondrial readiness — capable of doing anything useful with what you're putting in?

A supplement dropped into an overburdened biological system is not a gift. It is more load. More for the liver to process, more for the lymph to move, more molecular traffic in a network already congested. The analogy I keep returning to is pouring premium fuel into an engine with a blocked exhaust. The quality of the fuel is not the problem. The problem is that nothing can move.

I believe in targeted, evidence-informed supplementation, but the order of operations is everything. Drainage and clearance first. Then you build. Then you feed. Then you restore. A stack taken before the system can receive it is an expensive guess.

The Company

Renue by Science was founded around 2016–2017 by Bryan Nettles, a man who arrived at longevity science through the specific attention that serious illness creates. He recovered from prostate cancer and spent the years that followed building a company organised around a single commitment: bioavailability. Not just whether an ingredient has research support, but whether it can survive the journey through the human digestive system intact enough to do anything.

The company has gone through two name changes — Alive by Nature, then Alive by Science, then Renue by Science, the last two shifts forced by trademark litigation with an unrelated supplement brand. It is a small US-based operation with a research leadership team that includes a Research Director who co-authored a 2024 review in Metabolites on NMN supplementation, and a Chief Medical Advisor working in personalised longevity and epigenetic-based health strategies.

The entire product range is organised around a single biological question: how does cellular NAD+ decline with age, and what can be done about it from multiple angles at once?

The Credibility Audit

Renue's own quality claims are solid: ISO-certified and cGMP-certified lab testing on every batch, results published with lot numbers so you can verify before you buy, no artificial colours, sweeteners, or fillers, and a 60-day return guarantee. Independent reviewers at Innerbody Research, after two years of comparative testing across the NAD+ supplement landscape, rank Renue among the companies with the strongest third-party testing transparency in the space, with a certificate of analysis accessible on every product page.

The complicating data: a platform called SupplementChecker gives them a C-grade and flags that they don't hold certifications from NSF, USP, or Informed Sport — the gold-standard independent programmes that certify not just batch results but the entire manufacturing infrastructure. The Better Business Bureau carries a C+ rating, with some complaints around fulfilment and refund handling.

The tension is real. Renue commissions its own third-party batch testing — identity, purity, potency, lot by lot, results published. That is meaningful and not universal in this industry. What it is not is independent certification from NSF, USP, or Informed Sport, which verify the entire manufacturing infrastructure: raw material sourcing, facility standards, process controls, the chain of custody before anything reaches a capsule. Renue has the former. It does not yet have the latter. For someone who thinks carefully about what enters the body, that distinction warrants scrutiny — and here is what that scrutiny found. A clean COA on a specific batch tells you what was in that bottle. An NSF certification tells you something about the system that produced it. Both are evidence. They are not the same evidence. I looked at both, weighed them against the formula quality, the ingredient transparency, seven years without an FDA warning or recall, and what I have felt running this stack. I stayed with the brand. That is my assessment, not a recommendation to override your own.

NAD+ Complete

NAD+ Complete is where the stack begins.

NAD+ Complete is a liposomal blend of four compounds: NAD+ itself, NMN (nicotinamide mononucleotide), NR (nicotinamide riboside), and trigonelline. Our bodies manufacture NAD+ through multiple biosynthesis pathways; different precursors enter the chain at different points. Betting everything on one is less efficient than supplying the network simultaneously. NMN enters via the Preiss-Handler pathway; NR converts to NMN before doing the same; trigonelline — a naturally occurring alkaloid found in fenugreek and coffee — operates via a distinct third pathway, only recently characterised in published research. A 2023 study in Nature Metabolism identified trigonelline as a NAD+ precursor that declines with age in both humans and animal models, with supplementation shown to restore NAD+ levels in muscle tissue and improve mitochondrial function in aged mice. Human data are in early stages, but it is the most compelling new compound to enter this space in years — and the only formula currently combining it with NMN and NR in a single liposomal delivery.

NAD+ is a coenzyme involved in hundreds of metabolic reactions, from energy production to DNA repair to the activation of sirtuins — the proteins associated with longevity. By midlife, cellular NAD+ levels can fall by half. This decline is one of the better-established findings in ageing biology.

On delivery, the science is less settled. There are no large-scale published human trials demonstrating that liposomal NMN elevates NAD+ more effectively than standard oral NMN. Oral NMN is itself reasonably well absorbed — multiple human clinical trials confirm it effectively raises blood NAD+ concentrations. Renue commissioned a small double-blind study, fifteen male participants aged forty and older, which found an 84% increase in blood NAD+ levels after four weeks of liposomal NMN — sustained above baseline even four weeks after stopping — compared to a more modest increase in the standard NMN group. The directional finding is interesting. The sample size (five participants per group) is too small for certainty, and the study was company-funded.

What the broader liposomal literature does support: liposomal delivery systems likely produce higher peak plasma concentrations and a more sustained release curve than standard capsules. Whether this translates to meaningfully different health outcomes in humans remains unproven in head-to-head trials. For compounds like glutathione, where standard oral bioavailability is notoriously poor, the liposomal delivery rationale is considerably stronger than for NMN, which already absorbs reasonably well. The animal data — including a mouse study showing liposomal NMN produced NAD+ levels in liver tissue almost twice as high as standard NMN — is directionally consistent, if not definitive.

I take the NAD+ Complete because the multi-pathway logic is sound, the ingredient quality is verifiable, and the delivery technology represents a plausible advantage even where the human data is incomplete. I hold that last point lightly.

Senolytique

Senolytique sits on layered science and comes with caveats.

Senolytique contains fisetin, quercetin, and spermidine — compounds that target what biologists call senescent cells. Senescence is a state cells enter when they can no longer divide; healthy cellular biology clears them efficiently via autophagy and immune surveillance. With age, that clearance slows. Senescent cells accumulate, releasing inflammatory signalling molecules (the senescence-associated secretory phenotype, or SASP) that degrade the surrounding tissue environment. They are sometimes called zombie cells: not dead, not functional, and actively disruptive to everything around them.

Fisetin is, on current preclinical evidence, the strongest natural senolytic compound identified. A landmark paper in EBioMedicine showed it extends both median and maximum lifespan in mice and clears senescent cells more potently than other flavonoids tested. The first human clinical trial of senolytics — using dasatinib (a pharmaceutical) combined with quercetin — was published in the same journal and directly demonstrated that senolytic compounds can decrease senescent cells in humans. Quercetin alone has human meta-analysis data supporting reductions in inflammatory markers and cardiovascular risk. Spermidine operates through a different mechanism entirely: it is a naturally occurring polyamine that declines with age and induces autophagy — the cellular process by which the body degrades and recycles damaged components. Where fisetin and quercetin clear senescent cells, spermidine clears cellular debris more broadly. The two mechanisms are complementary rather than redundant, which is the logic of their combination here. Human data on spermidine remain limited, but the autophagy evidence in animal models is strong.

One dosing note: the spermidine in Senolytique sits at the lower end of meaningful dosing. If autophagy is a clinical priority — which in perimenopause and accelerated biological ageing it often is — Renue's standalone liposomal spermidine at 8mg is the stronger choice, either alongside or in place of the dose within this formula.

There is a layer of this science that supplement marketing omits, and it matters for a woman. Senolytic research has a significant gender bias: the majority of animal studies have been conducted on male models. The cognitive benefits of senolytic treatment — preserved memory, reduced neuroinflammation, slowed cognitive decline — have been demonstrated clearly in ageing male rats. Ageing female rats have not shown the same pattern. Oestrogen appears to modulate the senescent cell landscape in ways that make the systemic picture for women less predictable than the headline findings suggest.

The reproductive tissue data tells a different story. Spermidine has been shown to significantly increase autophagy markers and reduce senescence markers in female germline stem cells, and to ameliorate cellular senescence induced by oxidative stress via the PI3K/Akt pathway. Fisetin shows protective effects in female reproductive tissues. The picture is tissue-specific rather than uniformly positive or negative — which means the research is not a reason to avoid this formula, but it is a reason to hold the cognitive longevity claims with more nuance than the marketing applies to them, and to track your own response over time rather than extrapolating from studies that were not built around your biology.

Senolytics are not a daily supplement. The evidence base is built on intermittent use — a few days on, weeks off — because senescent cell clearance is an event, not a maintenance function. Clinical protocols use two to three consecutive days per month.

Energizer AM

The CD38 inhibitor formula.

CD38 is an enzyme whose activity increases substantially with age. Its role in our bodies is multifaceted — it is involved in immune function, calcium signalling, and cell communication — but one of its effects is that it consumes NAD+. It is, in the vocabulary of the Renue framework, a NAD+ thief. The older you get, the more CD38 activity you tend to have, and the faster your NAD+ is degraded.

Energizer AM contains resveratrol, CoQ10, green tea, and hesperidin. Resveratrol and the flavonoids in green tea and hesperidin have CD38 inhibitory properties documented in peer-reviewed research, including a 2013 paper published in Diabetes demonstrating that apigenin and quercetin inhibit CD38 activity in cells, producing measurable increases in intracellular NAD+. A subsequent study confirmed that quercetin's CD38 inhibitory activity preserves the cellular NAD+ pool and rescues cells from NAD+ depletion under conditions of DNA damage — the kind of oxidative damage that increases with age.

CoQ10 supports mitochondrial electron transport chain function — the machinery by which cells convert nutrients into ATP. Resveratrol activates SIRT1, a sirtuin that regulates gene expression, inflammation, and metabolic function. The evidence base for resveratrol has clear limits: strong in preclinical models, mixed in human trials, and most useful in combination with NMN rather than as a standalone.

The systems logic is compelling: not only producing more NAD+, but slowing the rate at which it is consumed. Production is not the central challenge — the drain is. CD38 consumes NAD+ faster than any precursor can replace it if left unchecked. Addressing only the supply while the drain accelerates is the biological equivalent of filling a bath without checking whether the plug is in.

Restore PM

The overnight formula: GABA, 5-HTP, apigenin, glutathione, and melatonin.

Sleep is our primary repair window. The cellular maintenance that cannot happen in the metabolic busyness of waking hours — the DNA repair, the glymphatic clearance of neurological waste, the protein refolding, the immune recalibration — takes place during sustained, structured sleep. A formula that supports sleep onset and sleep quality is foundational to a longevity stack.

GABA and 5-HTP support inhibitory neurotransmitter activity and serotonin precursor availability respectively. Melatonin in small doses (this formula uses a modest amount, appropriate for supporting the circadian signal without creating dependency) assists the sleep-wake transition. Apigenin is doing double duty here: it is a natural compound found abundantly in chamomile, with well-documented anxiolytic and sleep-facilitating properties via GABA-A receptor binding, and it is one of the CD38 inhibitors documented in the same Diabetes paper mentioned above — simultaneously supporting sleep and protecting NAD+ overnight.

Glutathione is the body's primary endogenous antioxidant, produced in the liver, critical to phase II detoxification. Oral glutathione in standard form has notoriously poor bioavailability — it is largely degraded in the gastrointestinal tract before reaching systemic circulation. Liposomal delivery is arguably strongest for glutathione of all the compounds in this stack, because the delivery problem here is genuine and well-documented. Overnight antioxidant support during the repair window is an appreciated advantage from a Total Load perspective.

Shield

Liposomal Vitamin C, calcium alpha-ketoglutarate (CaAKG), palmitoylethanolamide (PEA), and hyaluronic acid (HLA).

Where the rest of the stack focuses on NAD+ production and protection, Shield targets the factors that consume cellular resources — oxidative stress, inflammatory load, extracellular matrix degradation — from a different angle. It is also a recovery formula, not in the sports nutrition sense, but in the deeper sense of supporting the infrastructure the body uses to rebuild from daily load: oxidative clearance, inflammatory resolution, extracellular matrix turnover.

CaAKG is a Krebs cycle intermediate that has attracted significant interest in longevity research. A 2020 study in Cell Metabolism showed that alpha-ketoglutarate supplementation extended healthspan in mice. Human data is still emerging, but the mechanistic logic — that a central TCA-cycle metabolite involved in energy metabolism, collagen synthesis, epigenetic regulation, and the autophagy pathways that ageing tends to slow — is well-grounded in biochemistry.

PEA (palmitoylethanolamide) is a naturally occurring fatty acid amide the body produces itself. Its primary function is quieting the background — the chronic low-grade inflammatory tone that accumulates with age, regulating the signalling and the cleanup that follows. It works on receptors involved in pain regulation and neuroinflammation and has a reasonable evidence base in conditions of chronic inflammatory load. For anyone navigating perimenopause — a period of elevated inflammatory signalling, shifting immune regulation, and heightened neurological sensitivity — this is a beneficial inclusion.

Liposomal Vitamin C supports antioxidant defence, immune function, collagen synthesis, and adrenal health — and specifically helps steady the NAD+/NADH redox ratio that mitochondrial function depends on. The liposomal form matters here because Vitamin C bioavailability from standard oral supplementation plateaus and declines at higher doses; liposomal delivery extends the absorption curve.

HLA (hyaluronic acid) supports the extracellular matrix — the connective tissue environment of joints, skin, and eyes. It is among the less dramatic ingredients in the stack in terms of longevity science, but it is among the most immediately felt.

The Research Was Not Built Around Women

The longevity supplement industry has a problem. The foundational research — the animal studies, the mechanism work, the preclinical evidence that underpins most of what gets sold as anti-ageing intervention — was conducted predominantly on male subjects. In neuroscience, the discipline most relevant to cognitive longevity, male animal studies outnumber female studies 5.5 to 1. That bias has increased in non-human research over the past half-century, even as human clinical trial inclusion has slowly improved. The justification given was hormonal complexity: the female oestrous cycle was assumed to introduce variability that would complicate study design. The assumption has since been disproved — female animals are no more variable than males when oestrous staging is controlled — but the decades of male-default research cannot be undone.

The result is a supplement industry built largely on findings that were never tested on female biology, then marketed to women as though that distinction does not exist. A longevity stack that extends lifespan in male mice, reduces inflammation in male rats, and preserves cognitive function in male animal models is not automatically applicable to a woman in perimenopause with a different hormonal architecture, a different inflammatory profile, and a different NAD+ metabolism. Assuming it is has been the unexamined default.

The reason this stack holds up under that scrutiny is that the NAD+ precursor literature has an unusually strong female-specific thread running through it that longevity marketing consistently ignores.

Long-term NMN treatment increased median lifespan by 8.5% in female mice — an effect not replicated in male mice. Female mice also showed greater Preiss-Handler pathway metabolism than males, suggesting sex-specific differences in how NMN is converted to NAD+ that may actually favour women's biology. In human trials, NMN improved insulin sensitivity specifically in postmenopausal women. The sex-specific efficacy points particularly toward metabolic health — one of the central vulnerabilities of the menopausal transition. NAD+ levels in oocytes decline with age, and restoring NAD+ via NMN has been shown to improve egg quality and ovulation rates in female animal models. Women with PMOS — polyendocrine metabolic ovarian syndrome, recently renamed from PCOS to better reflect its metabolic and endocrine complexity — show lower NAD+ levels in ovarian cells, with NAD+ precursor supplementation producing measurable improvements in ovarian function.

The CD38 mechanism in Energizer AM is directly relevant to female hormonal biology in a way the product labelling does not make explicit. Oestrogen suppresses CD38 activity. As oestrogen declines in perimenopause, CD38 accelerates — the drain on NAD+ speeds up precisely as the capacity to produce it is already falling. Inhibiting CD38 in this transition addresses the specific driver of accelerated NAD+ loss in female biology, a mechanism with acute relevance to women in midlife.

The glutathione in Restore PM follows the same logic. Glutathione synthesis declines with oestrogen loss. The overnight liposomal delivery addresses a documented female-specific deficit at the biological moment — sleep, repair, clearance — when that deficit is most consequential.

The senolytics picture, as covered in the Senolytique section, is more tissue-specific — reproductive tissue responds well; systemic cognitive benefits are less reliably demonstrated in female models. That nuance belongs in the full picture. The NAD+ architecture of this stack — precursor supply, CD38 protection, overnight antioxidant restoration — lands on the right side of what female-specific research actually supports. Understanding the mechanisms is what makes it possible to know that.

The Perimenopause Dimension

None of this stack was designed specifically for women in midlife transition, but the biology maps onto perimenopause.

NAD+ decline accelerates in the menopausal transition. Oestrogen plays a role in NAD+ biosynthesis — as oestrogen drops, so does the enzymatic efficiency of NAD+ production, compounding the age-related decline already underway. Simultaneously, CD38 activity increases as immune regulation shifts — meaning the drain accelerates at exactly the moment supply is falling. The fatigue, cognitive fog, and loss of physical resilience that so many women attribute to hormonal change have a significant mitochondrial and NAD+ component that hormone therapy alone does not address.

Sleep disruption in perimenopause is not simply a matter of night sweats interrupting rest. The neurological architecture of sleep changes: lighter stages, reduced slow-wave depth, more frequent micro-arousals. The GABAergic and serotonergic support in Restore PM is directly relevant to this; so is the apigenin, which modulates GABA-A receptors in a way that addresses the heightened neurological arousal of this transition without the dependency profile of pharmaceutical sleep aids.

Glutathione production declines with oestrogen loss, reducing the body's antioxidant capacity at the same time oxidative stress increases. The overnight liposomal delivery in Restore PM addresses a documented female-specific deficit at the biological moment — sleep, repair, clearance — when that deficit is most consequential.

PEA in Shield addresses the neuroinflammatory component — the heightened pain sensitivity, the nervous system reactivity, the low-grade inflammatory burden that accumulates as oestrogen's anti-inflammatory signalling diminishes. The same terrain, approached from multiple angles.

How I Take It

Morning, with the first meal of the day or within thirty minutes of eating: NAD+ Complete and Energizer AM. Both contain compounds with mild stimulating properties — NAD+ and resveratrol specifically — and taking them late in the day can affect sleep onset in sensitive individuals. Shield goes here too; the Vitamin C and CaAKG have no timing sensitivity but there is no reason to split them unnecessarily.

Senolytique is not daily. Two to three consecutive days per month, aligned with a lower-demand period in the schedule. The mechanism is event-based clearance, not continuous maintenance — daily use does not improve the outcome and may blunt it.

Restore PM thirty to forty-five minutes before sleep. The melatonin, apigenin, and GABA need time to cross into effect before the sleep window, not during it.

A Note on Who This Is Not For

Several compounds in this stack have interactions that warrant attention. Quercetin and resveratrol — present in both Senolytique and Energizer AM — can potentiate the effects of blood-thinning medications including warfarin; anyone on anticoagulants should discuss supplementation with their prescribing physician before starting. Flavonoids including apigenin and quercetin have mild oestrogenic activity in some models; anyone with a hormone-sensitive condition should flag this with their clinical team. This stack is not appropriate during pregnancy or breastfeeding.

Before You Add Anything

The Total Load framework treats the accumulation of inputs, including therapeutic inputs, as a form of burden on the biological system. More is more load.

The supplements here are chosen with specific intent within a system designed first for drainage, clearance, and foundational terrain. Before adding this stack, the work was Tier Zero: the biological readiness beneath any intervention. Gut integrity. Lymphatic flow. Liver capacity. Mitochondrial membrane health — the infrastructure that determines whether a liposomal supplement can deliver its payload to the right destination.

A NAD+ precursor taken by someone with compromised mitochondrial membrane health, a sluggish lymphatic system, and a liver already overwhelmed by environmental toxin load is not going to produce the outcomes the research predicts. The research is conducted in controlled conditions on participants whose basic terrain has been assessed. People taking supplements have largely not assessed their terrain.

The caveat applies to any supplement company, including Renue — and it is not specific to them. They are producing good products, with transparent quality controls, real science behind the mechanisms, and a systems-level approach to NAD+ that is more coherent than much of what exists in this category. The liposomal delivery question has unresolved human evidence but sound mechanistic logic. The ingredient quality is verifiable. The formula architecture — boost, protect, clear, restore — reflects a real understanding of the biology.

And still: the most important supplement decision is to ask, before adding anything, whether the body has what it needs to receive it.

Release first. Then nourish.

Everything else follows.

Michelle Saram is a Regenerative Living Architect and founder of Michelle Clean Living. Her work on biological terrain, cellular health, and the Total Load framework is published on Substack The NAD+ Stack

A deep-dive into Renue by Science and the NAD+ stack I've been using since 2024

The Michelle Edit | Michelle Saram

There is a version of this essay that begins with the supplements. The ingredients, the mechanisms, the peer-reviewed citations stacked like evidence at a trial. I have spent considerable time going into the research.

But I want to begin somewhere else.

Does your body know how to receive this?

Is the ingredient pure? Does the mechanism make biological sense? Is the internal environment — the drainage, the detoxification, the cellular membrane integrity, the mitochondrial readiness — capable of doing anything useful with what you're putting in?

A supplement dropped into an overburdened biological system is not a gift. It is more load. More for the liver to process, more for the lymph to move, more molecular traffic in a network already congested. The analogy I keep returning to is pouring premium fuel into an engine with a blocked exhaust. The quality of the fuel is not the problem. The problem is that nothing can move.

I believe in targeted, evidence-informed supplementation, but the order of operations is everything. Drainage and clearance first. Then you build. Then you feed. Then you restore. A stack taken before the system can receive it is an expensive guess.

The Company

Renue by Science was founded around 2016–2017 by Bryan Nettles, a man who arrived at longevity science through the specific attention that serious illness creates. He recovered from prostate cancer and spent the years that followed building a company organised around a single commitment: bioavailability. Not just whether an ingredient has research support, but whether it can survive the journey through the human digestive system intact enough to do anything.

The company has gone through two name changes — Alive by Nature, then Alive by Science, then Renue by Science, the last two shifts forced by trademark litigation with an unrelated supplement brand. It is a small US-based operation with a research leadership team that includes a Research Director who co-authored a 2024 review in Metabolites on NMN supplementation, and a Chief Medical Advisor working in personalised longevity and epigenetic-based health strategies.

The entire product range is organised around a single biological question: how does cellular NAD+ decline with age, and what can be done about it from multiple angles at once?

The Credibility Audit

Renue's own quality claims are solid: ISO-certified and cGMP-certified lab testing on every batch, results published with lot numbers so you can verify before you buy, no artificial colours, sweeteners, or fillers, and a 60-day return guarantee. Independent reviewers at Innerbody Research, after two years of comparative testing across the NAD+ supplement landscape, rank Renue among the companies with the strongest third-party testing transparency in the space, with a certificate of analysis accessible on every product page.

The complicating data: a platform called SupplementChecker gives them a C-grade and flags that they don't hold certifications from NSF, USP, or Informed Sport — the gold-standard independent programmes that certify not just batch results but the entire manufacturing infrastructure. The Better Business Bureau carries a C+ rating, with some complaints around fulfilment and refund handling.

The tension is real. Renue commissions its own third-party batch testing — identity, purity, potency, lot by lot, results published. That is meaningful and not universal in this industry. What it is not is independent certification from NSF, USP, or Informed Sport, which verify the entire manufacturing infrastructure: raw material sourcing, facility standards, process controls, the chain of custody before anything reaches a capsule. Renue has the former. It does not yet have the latter. For someone who thinks carefully about what enters the body, that distinction warrants scrutiny — and here is what that scrutiny found. A clean COA on a specific batch tells you what was in that bottle. An NSF certification tells you something about the system that produced it. Both are evidence. They are not the same evidence. I looked at both, weighed them against the formula quality, the ingredient transparency, seven years without an FDA warning or recall, and what I have felt running this stack. I stayed with the brand. That is my assessment, not a recommendation to override your own.

NAD+ Complete

NAD+ Complete is where the stack begins.

NAD+ Complete is a liposomal blend of four compounds: NAD+ itself, NMN (nicotinamide mononucleotide), NR (nicotinamide riboside), and trigonelline. Our bodies manufacture NAD+ through multiple biosynthesis pathways; different precursors enter the chain at different points. Betting everything on one is less efficient than supplying the network simultaneously. NMN enters via the Preiss-Handler pathway; NR converts to NMN before doing the same; trigonelline — a naturally occurring alkaloid found in fenugreek and coffee — operates via a distinct third pathway, only recently characterised in published research. A 2023 study in Nature Metabolism identified trigonelline as a NAD+ precursor that declines with age in both humans and animal models, with supplementation shown to restore NAD+ levels in muscle tissue and improve mitochondrial function in aged mice. Human data are in early stages, but it is the most compelling new compound to enter this space in years — and the only formula currently combining it with NMN and NR in a single liposomal delivery.

NAD+ is a coenzyme involved in hundreds of metabolic reactions, from energy production to DNA repair to the activation of sirtuins — the proteins associated with longevity. By midlife, cellular NAD+ levels can fall by half. This decline is one of the better-established findings in ageing biology.

On delivery, the science is less settled. There are no large-scale published human trials demonstrating that liposomal NMN elevates NAD+ more effectively than standard oral NMN. Oral NMN is itself reasonably well absorbed — multiple human clinical trials confirm it effectively raises blood NAD+ concentrations. Renue commissioned a small double-blind study, fifteen male participants aged forty and older, which found an 84% increase in blood NAD+ levels after four weeks of liposomal NMN — sustained above baseline even four weeks after stopping — compared to a more modest increase in the standard NMN group. The directional finding is interesting. The sample size (five participants per group) is too small for certainty, and the study was company-funded.

What the broader liposomal literature does support: liposomal delivery systems likely produce higher peak plasma concentrations and a more sustained release curve than standard capsules. Whether this translates to meaningfully different health outcomes in humans remains unproven in head-to-head trials. For compounds like glutathione, where standard oral bioavailability is notoriously poor, the liposomal delivery rationale is considerably stronger than for NMN, which already absorbs reasonably well. The animal data — including a mouse study showing liposomal NMN produced NAD+ levels in liver tissue almost twice as high as standard NMN — is directionally consistent, if not definitive.

I take the NAD+ Complete because the multi-pathway logic is sound, the ingredient quality is verifiable, and the delivery technology represents a plausible advantage even where the human data is incomplete. I hold that last point lightly.

Senolytique

Senolytique sits on layered science and comes with caveats.

Senolytique contains fisetin, quercetin, and spermidine — compounds that target what biologists call senescent cells. Senescence is a state cells enter when they can no longer divide; healthy cellular biology clears them efficiently via autophagy and immune surveillance. With age, that clearance slows. Senescent cells accumulate, releasing inflammatory signalling molecules (the senescence-associated secretory phenotype, or SASP) that degrade the surrounding tissue environment. They are sometimes called zombie cells: not dead, not functional, and actively disruptive to everything around them.

Fisetin is, on current preclinical evidence, the strongest natural senolytic compound identified. A landmark paper in EBioMedicine showed it extends both median and maximum lifespan in mice and clears senescent cells more potently than other flavonoids tested. The first human clinical trial of senolytics — using dasatinib (a pharmaceutical) combined with quercetin — was published in the same journal and directly demonstrated that senolytic compounds can decrease senescent cells in humans. Quercetin alone has human meta-analysis data supporting reductions in inflammatory markers and cardiovascular risk. Spermidine operates through a different mechanism entirely: it is a naturally occurring polyamine that declines with age and induces autophagy — the cellular process by which the body degrades and recycles damaged components. Where fisetin and quercetin clear senescent cells, spermidine clears cellular debris more broadly. The two mechanisms are complementary rather than redundant, which is the logic of their combination here. Human data on spermidine remain limited, but the autophagy evidence in animal models is strong.

One dosing note: the spermidine in Senolytique sits at the lower end of meaningful dosing. If autophagy is a clinical priority — which in perimenopause and accelerated biological ageing it often is — Renue's standalone liposomal spermidine at 8mg is the stronger choice, either alongside or in place of the dose within this formula.

There is a layer of this science that supplement marketing omits, and it matters for a woman. Senolytic research has a significant gender bias: the majority of animal studies have been conducted on male models. The cognitive benefits of senolytic treatment — preserved memory, reduced neuroinflammation, slowed cognitive decline — have been demonstrated clearly in ageing male rats. Ageing female rats have not shown the same pattern. Oestrogen appears to modulate the senescent cell landscape in ways that make the systemic picture for women less predictable than the headline findings suggest.

The reproductive tissue data tells a different story. Spermidine has been shown to significantly increase autophagy markers and reduce senescence markers in female germline stem cells, and to ameliorate cellular senescence induced by oxidative stress via the PI3K/Akt pathway. Fisetin shows protective effects in female reproductive tissues. The picture is tissue-specific rather than uniformly positive or negative — which means the research is not a reason to avoid this formula, but it is a reason to hold the cognitive longevity claims with more nuance than the marketing applies to them, and to track your own response over time rather than extrapolating from studies that were not built around your biology.

Senolytics are not a daily supplement. The evidence base is built on intermittent use — a few days on, weeks off — because senescent cell clearance is an event, not a maintenance function. Clinical protocols use two to three consecutive days per month.

Energizer AM

The CD38 inhibitor formula.

CD38 is an enzyme whose activity increases substantially with age. Its role in our bodies is multifaceted — it is involved in immune function, calcium signalling, and cell communication — but one of its effects is that it consumes NAD+. It is, in the vocabulary of the Renue framework, a NAD+ thief. The older you get, the more CD38 activity you tend to have, and the faster your NAD+ is degraded.

Energizer AM contains resveratrol, CoQ10, green tea, and hesperidin. Resveratrol and the flavonoids in green tea and hesperidin have CD38 inhibitory properties documented in peer-reviewed research, including a 2013 paper published in Diabetes demonstrating that apigenin and quercetin inhibit CD38 activity in cells, producing measurable increases in intracellular NAD+. A subsequent study confirmed that quercetin's CD38 inhibitory activity preserves the cellular NAD+ pool and rescues cells from NAD+ depletion under conditions of DNA damage — the kind of oxidative damage that increases with age.

CoQ10 supports mitochondrial electron transport chain function — the machinery by which cells convert nutrients into ATP. Resveratrol activates SIRT1, a sirtuin that regulates gene expression, inflammation, and metabolic function. The evidence base for resveratrol has clear limits: strong in preclinical models, mixed in human trials, and most useful in combination with NMN rather than as a standalone.

The systems logic is compelling: not only producing more NAD+, but slowing the rate at which it is consumed. Production is not the central challenge — the drain is. CD38 consumes NAD+ faster than any precursor can replace it if left unchecked. Addressing only the supply while the drain accelerates is the biological equivalent of filling a bath without checking whether the plug is in.

Restore PM

The overnight formula: GABA, 5-HTP, apigenin, glutathione, and melatonin.

Sleep is our primary repair window. The cellular maintenance that cannot happen in the metabolic busyness of waking hours — the DNA repair, the glymphatic clearance of neurological waste, the protein refolding, the immune recalibration — takes place during sustained, structured sleep. A formula that supports sleep onset and sleep quality is foundational to a longevity stack.

GABA and 5-HTP support inhibitory neurotransmitter activity and serotonin precursor availability respectively. Melatonin in small doses (this formula uses a modest amount, appropriate for supporting the circadian signal without creating dependency) assists the sleep-wake transition. Apigenin is doing double duty here: it is a natural compound found abundantly in chamomile, with well-documented anxiolytic and sleep-facilitating properties via GABA-A receptor binding, and it is one of the CD38 inhibitors documented in the same Diabetes paper mentioned above — simultaneously supporting sleep and protecting NAD+ overnight.

Glutathione is the body's primary endogenous antioxidant, produced in the liver, critical to phase II detoxification. Oral glutathione in standard form has notoriously poor bioavailability — it is largely degraded in the gastrointestinal tract before reaching systemic circulation. Liposomal delivery is arguably strongest for glutathione of all the compounds in this stack, because the delivery problem here is genuine and well-documented. Overnight antioxidant support during the repair window is an appreciated advantage from a Total Load perspective.

Shield

Liposomal Vitamin C, calcium alpha-ketoglutarate (CaAKG), palmitoylethanolamide (PEA), and hyaluronic acid (HLA).

Where the rest of the stack focuses on NAD+ production and protection, Shield targets the factors that consume cellular resources — oxidative stress, inflammatory load, extracellular matrix degradation — from a different angle.

CaAKG is a Krebs cycle intermediate that has attracted significant interest in longevity research. A 2020 study in Cell Metabolism showed that alpha-ketoglutarate supplementation extended healthspan in mice. Human data is still emerging, but the mechanistic logic — that a Krebs cycle intermediate involved in energy metabolism, collagen synthesis, and epigenetic regulation might support cellular function with age — is well-grounded in biochemistry.

PEA (palmitoylethanolamide) is a naturally occurring fatty acid amide that modulates inflammatory responses, particularly in the nervous system. It works on receptors involved in pain regulation and neuroinflammation and has a reasonable evidence base in conditions of chronic inflammatory load. For anyone navigating perimenopause — a period of elevated inflammatory signalling, shifting immune regulation, and heightened neurological sensitivity — this is a beneficial inclusion.

Liposomal Vitamin C supports antioxidant defence, immune function, collagen synthesis, and adrenal health. The liposomal form matters here because Vitamin C bioavailability from standard oral supplementation plateaus and declines at higher doses; liposomal delivery extends the absorption curve.

HLA (hyaluronic acid) supports the extracellular matrix — the connective tissue environment of joints, skin, and eyes. It is among the less dramatic ingredients in the stack in terms of longevity science, but often immediately felt.

The Research Was Not Built Around Women

The longevity supplement industry has a problem. The foundational research — the animal studies, the mechanism work, the preclinical evidence that underpins most of what gets sold as anti-ageing intervention — was conducted predominantly on male subjects. In neuroscience, the discipline most relevant to cognitive longevity, male animal studies outnumber female studies 5.5 to 1. That bias has increased in non-human research over the past half-century, even as human clinical trial inclusion has slowly improved. The justification given was hormonal complexity: the female oestrous cycle was assumed to introduce variability that would complicate study design. The assumption has since been disproved — female animals are no more variable than males when oestrous staging is controlled — but the decades of male-default research cannot be undone.

The result is a supplement industry built largely on findings that were never tested on female biology, then marketed to women as though that distinction does not exist. A longevity stack that extends lifespan in male mice, reduces inflammation in male rats, and preserves cognitive function in male animal models is not automatically applicable to a woman in perimenopause with a different hormonal architecture, a different inflammatory profile, and a different NAD+ metabolism. Assuming it is has been the unexamined default.

The reason this stack holds up under that scrutiny is that the NAD+ precursor literature has an unusually strong female-specific thread running through it that longevity marketing consistently ignores.

Long-term NMN treatment increased median lifespan by 8.5% in female mice — an effect not replicated in male mice. Female mice also showed greater Preiss-Handler pathway metabolism than males, suggesting sex-specific differences in how NMN is converted to NAD+ that may actually favour women's biology. In human trials, NMN improved insulin sensitivity specifically in postmenopausal women. The sex-specific efficacy points particularly toward metabolic health — one of the central vulnerabilities of the menopausal transition. NAD+ levels in oocytes decline with age, and restoring NAD+ via NMN has been shown to improve egg quality and ovulation rates in female animal models. Women with PMOS — polyendocrine metabolic ovarian syndrome, recently renamed from PCOS to better reflect its metabolic and endocrine complexity — show lower NAD+ levels in ovarian cells, with NAD+ precursor supplementation producing measurable improvements in ovarian function.

The CD38 mechanism in Energizer AM is directly relevant to female hormonal biology in a way the product labelling does not make explicit. Oestrogen suppresses CD38 activity. As oestrogen declines in perimenopause, CD38 accelerates — the drain on NAD+ speeds up precisely as the capacity to produce it is already falling. Inhibiting CD38 in this transition addresses the specific driver of accelerated NAD+ loss in female biology, a mechanism with acute relevance to women in midlife.

The glutathione in Restore PM follows the same logic. Glutathione synthesis declines with oestrogen loss. The overnight liposomal delivery addresses a documented female-specific deficit at the biological moment — sleep, repair, clearance — when that deficit is most consequential.

The senolytics picture, as covered in the Senolytique section, is more tissue-specific — reproductive tissue responds well; systemic cognitive benefits are less reliably demonstrated in female models. That nuance belongs in the full picture. The NAD+ architecture of this stack — precursor supply, CD38 protection, overnight antioxidant restoration — lands on the right side of what female-specific research actually supports. Understanding the mechanisms is what makes it possible to know that.

The Perimenopause Dimension

None of this stack was designed specifically for women in midlife transition, but the biology maps onto perimenopause.

NAD+ decline accelerates in the menopausal transition. Oestrogen plays a role in NAD+ biosynthesis — as oestrogen drops, so does the enzymatic efficiency of NAD+ production, compounding the age-related decline already underway. Simultaneously, CD38 activity increases as immune regulation shifts — meaning the drain accelerates at exactly the moment supply is falling. The fatigue, cognitive fog, and loss of physical resilience that so many women attribute to hormonal change have a significant mitochondrial and NAD+ component that hormone therapy alone does not address.

Sleep disruption in perimenopause is not simply a matter of night sweats interrupting rest. The neurological architecture of sleep changes: lighter stages, reduced slow-wave depth, more frequent micro-arousals. The GABAergic and serotonergic support in Restore PM is directly relevant to this; so is the apigenin, which modulates GABA-A receptors in a way that addresses the heightened neurological arousal of this transition without the dependency profile of pharmaceutical sleep aids.

Glutathione production declines with oestrogen loss, reducing the body's antioxidant capacity at the same time oxidative stress increases. The overnight liposomal delivery in Restore PM addresses a documented female-specific deficit at the biological moment — sleep, repair, clearance — when that deficit is most consequential.

PEA in Shield addresses the neuroinflammatory component — the heightened pain sensitivity, the nervous system reactivity, the low-grade inflammatory burden that accumulates as oestrogen's anti-inflammatory signalling diminishes. The same terrain, approached from multiple angles.

How I Take It

Morning, with the first meal of the day or within thirty minutes of eating: NAD+ Complete and Energizer AM. Both contain compounds with mild stimulating properties — NAD+ and resveratrol specifically — and taking them late in the day can affect sleep onset in sensitive individuals. Shield goes here too; the Vitamin C and CaAKG have no timing sensitivity but there is no reason to split them unnecessarily.

Senolytique is not daily. Two to three consecutive days per month, aligned with a lower-demand period in the schedule. The mechanism is event-based clearance, not continuous maintenance — daily use does not improve the outcome and may blunt it.

Restore PM thirty to forty-five minutes before sleep. The melatonin, apigenin, and GABA need time to cross into effect before the sleep window, not during it.

A Note on Who This Is Not For

Several compounds in this stack have interactions that warrant attention. Quercetin and resveratrol — present in both Senolytique and Energizer AM — can potentiate the effects of blood-thinning medications including warfarin; anyone on anticoagulants should discuss supplementation with their prescribing physician before starting. Flavonoids including apigenin and quercetin have mild oestrogenic activity in some models; anyone with a hormone-sensitive condition should flag this with their clinical team. This stack is not appropriate during pregnancy or breastfeeding.

Before You Add Anything

The Total Load framework treats the accumulation of inputs, including therapeutic inputs, as a form of burden on the biological system. More is more load.

The supplements here are chosen with specific intent within a system designed first for drainage, clearance, and foundational terrain. Before adding this stack, the work was Tier Zero: the biological readiness beneath any intervention. Gut integrity. Lymphatic flow. Liver capacity. Mitochondrial membrane health — the infrastructure that determines whether a liposomal supplement can deliver its payload to the right destination.

A NAD+ precursor taken by someone with compromised mitochondrial membrane health, a sluggish lymphatic system, and a liver already overwhelmed by environmental toxin load is not going to produce the outcomes the research predicts. The research is conducted in controlled conditions on participants whose basic terrain has been assessed. People taking supplements have largely not assessed their terrain.

The caveat applies to any supplement company, including Renue — and it is not specific to them. They are producing good products, with transparent quality controls, real science behind the mechanisms, and a systems-level approach to NAD+ that is more coherent than much of what exists in this category. The liposomal delivery question has unresolved human evidence but sound mechanistic logic. The ingredient quality is verifiable. The formula architecture — boost, protect, clear, restore — reflects a real understanding of the biology.

And still: the most important supplement decision is to ask, before adding anything, whether the body has what it needs to receive it.

Release first. Then nourish.

Everything else follows.

Michelle Saram is a Regenerative Living Architect and founder of Michelle Clean Living. Her work on biological terrain, cellular health, and the Total Load framework is published on Substack https://substack.com/@michellesaram.

This essay is personal and educational in nature and does not constitute medical advice.

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