Senolytics, NAD+, and the New Science of Longevity

The Zombie Cell Problem

Inside your body right now, there are cells that have stopped dividing but refuse to die. They sit in your tissues — fat, skin, joints, lungs, blood vessels — secreting a toxic cocktail of inflammatory molecules, tissue-degrading enzymes, and growth factors that corrupt their neighbors. Scientists call them senescent cells. A more honest name is zombie cells.

In small numbers and temporarily, senescent cells serve a purpose. They halt damaged cells from becoming cancerous. They help with wound healing and embryonic development. But with age, they accumulate — because the immune system that should clear them loses its edge, and the signals that should trigger their removal get drowned out by chronic inflammation. By your 60s and 70s, senescent cells have colonized virtually every organ system, and their secretions — collectively called the senescence-associated secretory phenotype, or SASP — are driving much of what we call aging.

The SASP is not subtle. It includes IL-6, IL-1beta, TNF-alpha, MMP-3, VEGF, and dozens more. It degrades the extracellular matrix, promotes fibrosis, triggers inflammation in neighboring cells, impairs stem cell function, and even induces senescence in healthy cells nearby. One rotten apple genuinely spoils the barrel.

This is where senolytics enter the picture — compounds that selectively destroy senescent cells while leaving healthy cells intact.

The Senolytic Revolution

Dasatinib + Quercetin (D+Q)

The pioneering senolytic combination came from James Kirkland’s lab at the Mayo Clinic. In 2015, Zhu and colleagues published in Aging Cell showing that dasatinib (a leukemia drug that inhibits tyrosine kinases) combined with quercetin (a plant flavonoid that inhibits BCL-2 family survival pathways) could selectively kill senescent cells in mice and extend healthspan.

The key insight: senescent cells are addicted to pro-survival pathways. They’re damaged enough to trigger apoptosis, but they upregulate survival networks (BCL-2, PI3K/AKT, p21, serpins) to stay alive. Senolytics don’t poison healthy cells — they remove the life support that only zombie cells depend on.

The dosing protocol that has emerged from human trials:

• Dasatinib: 100mg
• Quercetin: 500-1000mg
• Schedule: 2-3 consecutive days per month (hit-and-run strategy)
• Not continuous — this is critical. Senescent cells take weeks to reaccumulate, so intermittent dosing provides benefit while minimizing side effects.

Kirkland’s group demonstrated in humans that D+Q improved physical function in patients with idiopathic pulmonary fibrosis (Justice 2019) and reduced senescent cell burden in diabetic kidney disease (Hickson 2019). The UNITY Biotechnology trials targeting senescent cells in osteoarthritis showed mixed results with their specific compound (UBX0101) but validated the concept.

Fisetin

Fisetin — a flavonoid found in strawberries, apples, and persimmons — emerged as a senolytic from Yousefzadeh’s 2018 study in EBioMedicine. In mice, fisetin extended median lifespan by about 10% even when given late in life. It reduced senescent cell markers, lowered SASP factors, and improved tissue function.

What makes fisetin compelling: it’s a natural compound with a strong safety profile, available without prescription. It has both senolytic and senomorphic properties (meaning it both kills senescent cells and modulates their secretions).

• Dosing: 500-1500mg for 2-3 consecutive days monthly (mirroring the hit-and-run approach)
• Form: Look for formulations with enhanced bioavailability (liposomal or with piperine)
• Can be used as an alternative to D+Q for those without access to dasatinib or wanting a gentler approach

Piperlongumine

Derived from the long pepper plant (Piper longum), piperlongumine selectively kills senescent cells by targeting oxidation resistance 1 (OXR1) and increasing reactive oxygen species specifically in damaged cells. It’s earlier in the research pipeline but represents another tool in the emerging senolytic toolkit.

NAD+: The Currency of Cellular Energy

If senescent cells are the zombies, then NAD+ (nicotinamide adenine dinucleotide) is the electricity. Every cell in your body depends on it for energy production, DNA repair, sirtuin activation, immune function, and circadian rhythm regulation. And it declines relentlessly with age.

David Sinclair’s lab at Harvard has been the most prominent voice on NAD+ biology. By age 50, your NAD+ levels may be half of what they were at 20. By 80, they may be 1-10% of youthful levels. This decline correlates with virtually every hallmark of aging.

What drives the decline? The enzyme CD38 — which increases with age and chronic inflammation — consumes NAD+ voraciously. DNA damage activates PARP enzymes that also drain the pool. And the biosynthetic pathways that produce NAD+ become less efficient.

NMN vs NR: The Precursor Debate

Two NAD+ precursors dominate the market:

NMN (Nicotinamide Mononucleotide)

• One step closer to NAD+ in the biosynthetic pathway
• Dose: 500-1000mg daily, taken in the morning (NAD+ has circadian rhythms — it should peak in the morning)
• The MIB-626 trial (Yi 2023) showed NMN safely increased blood NAD+ levels in humans
• Key study: Igarashi 2022 showed NMN improved muscle insulin sensitivity in prediabetic women
• Sinclair’s preferred precursor

NR (Nicotinamide Riboside)

• Commercially available as Niagen (ChromaDex/Tru Niagen)
• Dose: 300-600mg daily
• More human clinical trial data than NMN (Martens 2018 — improved vascular function in older adults)
• NICE trial showed NR reduced neuroinflammation markers in Parkinson’s disease (Brakedal 2022)
• Some evidence of higher bioavailability per milligram

The honest answer: both work. Both raise NAD+ levels in human studies. NMN may have a slight theoretical advantage (being one step closer to NAD+), but NR has more published human data. Some practitioners recommend cycling between them.

Timing matters: Take NAD+ precursors in the morning. NAD+ follows a circadian pattern, peaking during active hours. Taking them at night may disrupt sleep by interfering with circadian NAD+ rhythms.

CD38 inhibitors can amplify NAD+ boosting by reducing its breakdown: apigenin (found in parsley, chamomile), luteolin, and quercetin all inhibit CD38.

Sirtuins: The Longevity Regulators

NAD+ alone isn’t the full story. It’s the essential cofactor for sirtuins — a family of seven enzymes (SIRT1-7) that regulate DNA repair, inflammation, mitochondrial function, fat metabolism, and stress resistance. They’re sometimes called “longevity genes,” though they’re more accurately longevity regulators.

Sirtuins only function when NAD+ is available. This is why NAD+ decline has such far-reaching consequences — it silences the entire sirtuin network.

Resveratrol is the most studied sirtuin activator. Sinclair has long championed the combination of resveratrol + NMN as synergistic — resveratrol steps on the sirtuin accelerator while NMN provides the fuel (NAD+).

• Resveratrol dosing: 500-1000mg daily, taken with a fat-containing meal (it’s fat-soluble; bioavailability increases dramatically with dietary fat — Walle 2011)
• Trans-resveratrol is the active form — verify this on the supplement label
• Pterostilbene (found in blueberries) is a methylated form of resveratrol with 4x better bioavailability and longer half-life — 100-250mg daily as an alternative

Caloric restriction is the original sirtuin activator. Every organism studied — yeast, worms, flies, mice, primates — shows lifespan extension with caloric restriction. The mechanism runs partly through sirtuin activation via rising NAD+/NADH ratios.

AMPK: The Energy Sensor

AMPK (AMP-activated protein kinase) is the cellular fuel gauge. When energy is low (high AMP:ATP ratio), AMPK activates and shifts the cell from growth mode to repair mode. It stimulates autophagy, mitochondrial biogenesis, and glucose uptake while suppressing mTOR-driven growth signaling.

With age, AMPK sensitivity declines. The sensor gets sticky. Cells stay in growth mode even when they should be repairing.

Berberine is the functional medicine workhorse AMPK activator:

• 500mg, 2-3 times daily with meals
• Comparable to metformin in head-to-head trials for blood sugar reduction (Yin 2008)
• Also modifies the gut microbiome favorably
• Caution: can interact with CYP3A4-metabolized medications

Metformin — the diabetes drug repurposed for longevity:

• The TAME (Targeting Aging with Metformin) trial, led by Nir Barzilai at Albert Einstein College of Medicine, is the first FDA-approved clinical trial targeting aging itself
• Observational data: diabetics on metformin had lower all-cause mortality than non-diabetic controls (Bannister 2014)
• Dose: 500-1000mg daily, typically extended-release
• Controversy: may blunt some exercise adaptations (Konopka 2019) — some practitioners recommend not taking it on exercise days

Exercise is the most potent natural AMPK activator. A single bout of moderate-intensity exercise activates AMPK in skeletal muscle for hours. This alone accounts for many of exercise’s anti-aging effects.

mTOR: The Growth Switch

mTOR (mechanistic target of rapamycin) is the master growth regulator. When nutrients are abundant — especially protein and leucine — mTOR drives cell growth, protein synthesis, and proliferation. Essential in youth. Increasingly problematic in aging, when unrestrained growth signaling promotes cancer, suppresses autophagy, and accelerates cellular senescence.

Rapamycin — the most consistent life-extending drug in animal studies:

• The NIA’s Interventions Testing Program (ITP) showed rapamycin extended lifespan in mice at all test sites, by 9-14%, even when started late in life
• Mechanism: mTOR inhibition increases autophagy, reduces senescent cell burden, improves immune function (paradoxically — low-dose rapamycin improved vaccine responses in elderly humans, Mannick 2014)
• Human longevity dosing (off-label): 3-6mg once weekly (pulsed, not daily — this is critical for avoiding immunosuppression)
• Must be prescribed and monitored by a physician. Lipid panels and blood counts need tracking.

Periodic protein restriction mimics mTOR modulation without drugs:

• 1-2 days per week with protein intake below 15-20g
• Or Valter Longo’s fasting-mimicking diet (5 days monthly, ~800 calories, low protein)
• This allows mTOR to drop, autophagy to activate, and damaged proteins to be cleared

A Practical Longevity Stack

For the practitioner or informed individual assembling a protocol, here’s how these pieces fit together. This is not a universal prescription — it’s a framework for personalization.

Daily Foundation:

• NMN 500-1000mg (morning, empty stomach or with breakfast)
• Trans-resveratrol 500mg or pterostilbene 150mg (with a fat-containing meal)
• Berberine 500mg 2x daily with meals (or metformin 500-1000mg ER if prescribed)
• Quercetin 500mg daily (CD38 inhibition + mild senolytic effect)
• Spermidine 5-10mg (autophagy support) or wheat germ 2 tbsp

Monthly Senolytic Pulse (pick one):

• Fisetin 1000-1500mg for 2 consecutive days
• OR Quercetin 1000mg + dasatinib 100mg for 2 consecutive days (requires prescription for dasatinib)

Cycling:

• Rapamycin users: 5-6mg once weekly, cycle 8 weeks on, 2 weeks off (physician-supervised)
• Berberine/metformin: some practitioners cycle 5 days on, 2 off (skip exercise days)

Lifestyle Non-Negotiables:

• Time-restricted eating (at least 14-16 hour overnight fast)
• Vigorous exercise 3-4x/week (HIIT for mitochondria and AMPK; resistance for mTOR modulation)
• Sauna 3-4x/week if accessible (heat shock proteins, senescent cell clearance)
• Sleep 7-9 hours (NAD+ circadian optimization, growth hormone, autophagy)

The Paradigm Shift

What makes this moment in longevity science remarkable isn’t any single compound. It’s that we now understand the mechanisms well enough to intervene rationally. Senolytics clear the zombie cells. NAD+ precursors restore the energy currency. Sirtuin activators turn on the repair programs. AMPK activators shift the cell from growth to maintenance. mTOR modulation lets autophagy do its work.

These aren’t separate interventions — they’re a coordinated strategy targeting the same underlying biology from different angles. Like a team of surgeons in an operating room, each addressing their piece of the same patient.

The field is young. Most of this data comes from animal studies and early human trials. But the trajectory is clear, the mechanisms are validated, and the safety profiles of many of these compounds — quercetin, fisetin, NMN, berberine, resveratrol — are well-established from decades of use.

We’re not trying to live forever. We’re trying to compress the period of decline — to stay functional, sharp, and independent until close to the end. That’s healthspan, not just lifespan. And for the first time in human history, we have molecular tools to pursue it deliberately.

What if the years you feared most — the final decades — could actually be some of your strongest?