NAD+ Precursors: Boost Healthspan Without Calorie Cuts

By 2030, scientists predict that NAD+ supplementation could become as routine as taking vitamin D—but unlike most wellness trends, this one is backed by robust cellular biology. Imagine extending your healthy years without the grueling demands of calorie restriction or fasting. That future is already here, and it hinges on two molecules you've probably never heard of: nicotinamide riboside (NR) and nicotinamide mononucleotide (NMN). These NAD+ precursors are rewriting the longevity playbook, offering a practical pathway to cellular rejuvenation that busy adults can actually sustain.

NAD+—nicotinamide adenine dinucleotide—is a coenzyme found in every cell of your body. It powers the mitochondria, repairs DNA, and regulates the sirtuins, a family of proteins that act as cellular guardians against aging. But here's the catch: NAD+ levels plummet as we age, dropping by roughly 50% between ages 40 and 60. That decline fuels fatigue, metabolic dysfunction, inflammation, and a cascade of age-related diseases. For decades, calorie restriction has been the gold standard for boosting NAD+ and activating longevity pathways. Yet for most people, sustained fasting or severe dietary limits remain impractical—or downright miserable. Enter NR and NMN, two vitamin B3 derivatives that can elevate NAD+ without forcing you to skip meals or count every calorie.

The Breakthrough: Why NAD+ Matters for Aging and Health

In 2025, researchers at the University of Bergen made a stunning discovery: mitochondria don't just use NAD+—they store it like a rechargeable battery, releasing reserves during cellular stress. When those reserves run dry, cells lose their ability to repair DNA, produce energy, and resist inflammation. "NAD acts like a rechargeable battery storing energy retrieved from nutrients and then passing it on to fuel energy-demanding processes," explains Mathias Ziegler, MD, PhD, who led the study. "If mitochondria do not have enough NAD stored up, it can have a fatal consequence for the cell."

This mitochondrial NAD+ reservoir represents a distinct therapeutic target. Unlike blood NAD+, which fluctuates and may not reflect tissue-level status, mitochondrial NAD+ directly influences the cellular machinery that determines how well you age. Studies show that approximately 40–70% of total cellular NAD+ is concentrated within mitochondria, making them the epicenter of NAD+-dependent longevity pathways. When mitochondrial NAD+ drops, so does your capacity for DNA repair, oxidative metabolism, and sirtuin activation—the very processes that separate healthy aging from accelerated decline.

Human trials have confirmed what animal studies suggested: oral supplementation with NR or NMN can increase blood NAD+ levels by 40–90% within weeks. More importantly, these precursors reach target tissues—muscle, brain, heart—and improve metabolic markers such as insulin sensitivity, arterial stiffness, and mitochondrial biogenesis. A 2021 trial in prediabetic women showed that 250 mg of NMN daily for 10 weeks significantly improved insulin sensitivity and muscle insulin signaling. Another study in healthy older men found that 250 mg NMN over 12 weeks raised whole-blood NAD+ levels and modestly enhanced muscle performance. Meanwhile, NR at 1,000 mg daily has been shown to lower systolic blood pressure and reduce arterial stiffness in middle-aged adults.

What sets NAD+ precursors apart from direct NAD+ supplementation—or even IV infusions—is cellular uptake. NAD+ itself is a large, unstable molecule that cannot easily cross cell membranes. By contrast, NMN and NR are smaller, more stable, and equipped with dedicated transport mechanisms. In 2019, a Nature study identified the Slc12a8 transporter, which shuttles NMN directly into cells. NR, on the other hand, is converted to NMN inside cells before becoming NAD+. Both pathways work, but they do so via distinct routes—and that difference has profound implications for efficacy, bioavailability, and long-term safety.

Historical Perspective: From Calorie Restriction to Cellular Hacking

For nearly a century, scientists have known that reducing calorie intake extends lifespan in yeast, worms, mice, and primates. Calorie restriction (CR) increases NAD+ levels by 30–50% in animal models, activating sirtuins and enhancing DNA repair. The mechanism is elegant: when energy is scarce, cells upregulate NAMPT, the rate-limiting enzyme in NAD+ biosynthesis, and shift into a survival mode that prioritizes maintenance over growth. This metabolic reprogramming delays aging, reduces cancer risk, and improves cardiovascular health.

But CR comes with a price. Sustained calorie restriction demands discipline, can trigger fatigue and irritability, and may not be safe for everyone—especially those with chronic illness, low body weight, or high physical demands. Intermittent fasting offers a more feasible alternative, but even that requires careful planning and is difficult to maintain long-term. Enter NAD+ precursors: a way to mimic the cellular benefits of CR without the dietary sacrifice.

The discovery of NR and NMN as NAD+ boosters emerged from decades of research into vitamin B3 metabolism. Nicotinic acid (niacin) and nicotinamide (NAM) have long been known to raise NAD+, but both have drawbacks. Niacin causes uncomfortable flushing at therapeutic doses, and NAM inhibits sirtuins at high concentrations—counteracting the very pathways you're trying to activate. NR and NMN, by contrast, are sirtuin-friendly. They don't trigger flushing, and they elevate NAD+ without the methylation burden imposed by NAM. Early animal studies showed that NR supplementation in mice on a high-fat diet resulted in 60% less weight gain, improved oxidative metabolism, and enhanced sirtuin activity. These findings sparked a wave of human trials that continue to this day.

Yet the road from lab to clinic has been bumpy. NAD+ metabolism is complex, tissue-specific, and influenced by age, diet, inflammation, and genetic factors. Not all tissues respond equally to supplementation. Blood levels rise reliably, but muscle NAD+ may not—and that discrepancy has led to mixed results in strength and endurance trials. Moreover, regulatory uncertainty has complicated market access. In 2022, the FDA classified NMN as an investigational drug rather than a dietary supplement, limiting its availability in the U.S. NR, by contrast, has Generally Recognized as Safe (GRAS) status and is widely available. These regulatory distinctions reflect safety data, manufacturing practices, and the political economy of supplement approval—not necessarily differences in efficacy.

The Technology Explained: How NR and NMN Work

NAD+ biosynthesis occurs via three pathways: the de novo pathway (from tryptophan), the Preiss-Handler pathway (from nicotinic acid), and the salvage pathway (from nicotinamide and its derivatives). The salvage pathway is the dominant route in mammals, accounting for most daily NAD+ production. NAMPT converts nicotinamide to nicotinamide mononucleotide (NMN), and NMNAT enzymes then convert NMN to NAD+. NR enters this pathway upstream of NAMPT, bypassing the rate-limiting step. It is phosphorylated by nicotinamide riboside kinases (NRK1 and NRK2) to form NMN, which then proceeds to NAD+.

This biochemical choreography has practical consequences. Because NR bypasses NAMPT, it may be less effective at stimulating endogenous NAD+ synthesis—but more effective at rapidly boosting NAD+ when NAMPT activity is low (as in aging or inflammation). NMN, by contrast, depends on the Slc12a8 transporter for cellular entry. Once inside, it is quickly converted to NAD+ by NMNAT. Animal studies suggest that oral NMN reaches plasma within 2.5 minutes and elevates muscle NAD+ within 60 minutes. In contrast, NR is rapidly degraded in the bloodstream into nicotinamide (NAM), which then re-enters the salvage pathway—potentially diluting its tissue-specific effects.

The phosphate group on NMN appears critical for effective NAD+ boosting. This structural difference may explain why many biotech companies focus on NMN analogues and why NMN has shown superior tissue penetration in preclinical models. A 2021 study in the FASEB Journal found that 1,000 mg of NR daily increased blood NAD+ but failed to raise muscle NAD+, whereas NMN consistently elevated NAD+ in muscle, heart, and brain tissues in mice. NMN also activates SIRT3, a mitochondrial sirtuin, whereas NR does not—suggesting that NMN may have unique mitochondrial benefits.

However, NMN is vulnerable to extracellular degradation by CD38, an enzyme that consumes NAD+ and its precursors. CD38 activity increases with age and inflammation, potentially limiting NMN's effectiveness in older adults. Pharmacological inhibition of CD38—using compounds like CD38-IN-78c—can preserve NMN levels and enhance efficacy, but such strategies remain experimental. NR, being more stable in circulation, may be less susceptible to CD38 degradation, though it faces its own metabolic bottleneck: rapid conversion to NAM.

Formulation matters enormously. Standard oral capsules have bioavailability of 10–30%, meaning most of the dose never reaches your cells. Enteric-coated capsules improve this to 30–50% by protecting the precursor from stomach acid. Liposomal formulations, which encapsulate NMN or NR in lipid spheres, achieve 50–80% bioavailability by fusing directly with cell membranes. Nanoparticle formulations push this to 60–90%, but they also carry risks: excessive cellular uptake can overwhelm homeostatic controls, leading to unpredictable effects. Sublingual or buccal administration bypasses first-pass metabolism, enhancing bioavailability and potentially aligning dosing with circadian NAD+ fluctuations. A hybrid approach—dissolving half your dose under the tongue and swallowing the rest in an enhanced capsule—may offer the best of both worlds.

Reshaping Health: The Societal Promise and Practical Impact

If NAD+ precursors deliver on their promise, the implications extend far beyond individual health. Consider the healthcare burden of age-related metabolic disease: type 2 diabetes, cardiovascular disease, Alzheimer's, and frailty collectively cost trillions of dollars annually and account for the majority of morbidity in older adults. Even modest delays in disease onset—say, five years—could transform public health, reduce healthcare spending, and improve quality of life for billions. NAD+ supplementation won't replace healthy diet and exercise, but it could serve as a biochemical safety net, compensating for the inevitable decline in endogenous NAD+ production.

Already, athletes are using NAD+ boosters to enhance recovery and performance. Vitality+®, a commercial formulation combining NR, NMN, nicotinamide, creatine, and D-ribose, is used by elite competitors seeking rapid NAD+ restoration. In clinical trials, NR supplementation at 1,000 mg daily increased daily step counts in older adults—suggesting that NAD+ boosters may enhance not just cellular health but also physical activity engagement, creating a positive feedback loop. Similarly, NMN at 250 mg daily improved walking distance in a six-minute endurance test among middle-aged adults, with higher doses (600–900 mg) producing even greater gains.

Yet the benefits are not universal. A 24-week trial in older diabetic men found that NMN improved metabolic markers but did not significantly enhance grip strength or walking speed. A 2024 meta-analysis of 10 randomized controlled trials concluded that NMN and NR supplementation generally did not improve muscle strength or physical function in older adults. These findings underscore a critical point: cellular NAD+ is necessary but not sufficient for functional improvement. Muscle performance depends on neural drive, muscle mass, contractile proteins, and motivation—none of which are directly modulated by NAD+. Thus, NAD+ precursors are best viewed as metabolic optimizers, not performance enhancers.

The cognitive domain tells a similar story. An 8-week crossover trial in older adults with mild cognitive impairment found that NR at 1,000 mg daily reduced plasma phosphorylated tau 217 (pTau217) by 7%—a promising Alzheimer's biomarker—but did not improve cognitive test scores. Step counts increased during the NR phase, hinting at subtle behavioral or motivational effects, but memory and executive function remained unchanged. These results are both encouraging and sobering. They suggest that NAD+ boosters may influence early pathological processes without producing immediate symptomatic relief—a hallmark of preventive rather than curative interventions.

For busy adults seeking healthspan extension without calorie restriction, the value proposition is clear: take a daily capsule, support your cellular NAD+ reserves, and potentially delay the metabolic decline that precedes chronic disease. It's not a magic bullet, but it's a practical tool—and unlike fasting or extreme diets, it's sustainable.

Benefits and Opportunities: What the Science Actually Shows

Let's cut through the hype and focus on what NAD+ precursors can demonstrably do in humans:

Metabolic Health: NMN at 250 mg daily improves insulin sensitivity and muscle insulin signaling in prediabetic women. NR at 1,000 mg daily enhances metabolic markers in obese adults, reducing systolic blood pressure and arterial stiffness. These effects align with NAD+'s role in mitochondrial biogenesis and sirtuin activation, both of which enhance glucose uptake and fatty acid oxidation.

Cardiovascular Function: NR supplementation improves endothelial function, lowers blood pressure (particularly nighttime BP in those not on antihypertensives), and reduces pulse wave velocity—a marker of arterial stiffness. High doses (≥1,000 mg) appear necessary for cardiovascular benefit, and the effects are most pronounced in individuals with pre-existing hypertension or metabolic syndrome.

Inflammation and Immune Response: Multiple studies show that NR reduces circulating cytokines, suggesting an anti-inflammatory effect. This may reflect NAD+'s role in regulating PARPs and sirtuins, both of which modulate NF-κB signaling and immune cell function. In aging, chronic low-grade inflammation ("inflammaging") drives tissue dysfunction; dampening this inflammation could slow systemic decline.

Mitochondrial Biogenesis: Both NR and NMN increase markers of mitochondrial health, including SIRT3 activation, oxidative phosphorylation gene expression, and mitochondrial membrane potential. In a study of mesenchymal stem cells deficient in Werner syndrome protein (WRN), NR treatment for 24 hours restored mitochondrial gene expression and reduced cellular senescence from ~40% to <10%.

Cognitive and Neuroprotective Effects: While cognitive test scores have not improved in short-term trials, reductions in pTau217 and increases in step counts suggest that NR may influence brain health indirectly—through improved vascular function, reduced neuroinflammation, or enhanced neuronal resilience. Longer trials are needed to assess whether these biomarker changes translate into clinical benefit.

Energy and Physical Activity: Some users report increased energy and motivation, though placebo-controlled trials show mixed results. The increase in step counts during NR supplementation is intriguing and may reflect subtle improvements in mitochondrial ATP production or dopaminergic signaling.

Critically, NAD+ precursors appear safe. Short-term trials (up to 24 weeks) using NR up to 2,000 mg daily and NMN up to 1,200 mg daily report no serious adverse events. Common mild side effects include nausea, headache, digestive discomfort, and flushing—typically transient and dose-dependent. Long-term safety data are sparse, but the fact that NR is a naturally occurring trace nutrient in milk and yeast suggests a low risk of toxicity at physiological doses.

Risks and Challenges: What Could Go Wrong

No intervention is without risk, and NAD+ precursors are no exception. Here are the key concerns:

Methylation Burden: NAD+ metabolism generates nicotinamide (NAM), which must be methylated by nicotinamide N-methyltransferase (NNMT) for excretion. Chronic high-dose supplementation could deplete methyl donors (S-adenosylmethionine, or SAM), potentially impairing methylation-dependent processes like DNA methylation, neurotransmitter synthesis, and detoxification. This is why many NAD+ formulations include trimethylglycine (TMG) or betaine to replenish methyl groups.

NAMPT Suppression: Paradoxically, supplementation with NAD+ precursors may downregulate NAMPT, the endogenous enzyme that synthesizes NMN from nicotinamide. If supplementation is stopped abruptly, NAD+ levels could rebound lower than baseline. Exercise, by contrast, upregulates NAMPT by 127% within three weeks—suggesting that lifestyle interventions may be more sustainable long-term.

Cancer Risk: NAD+ fuels cellular processes, including those in cancer cells. Elevated NAD+ could theoretically support tumor growth or confer chemoresistance. A 2024 review noted that increased PARP and sirtuin activity in cancer cells can drive proliferation and survival, and recommended against NAD+ supplementation during active cancer treatment. However, no human trials have reported increased cancer incidence with NR or NMN.

Drug Interactions: NAD+ boosters can potentiate anticoagulants like warfarin, requiring INR monitoring. They may amplify the blood-pressure-lowering effects of antihypertensives, increasing hypotension risk. High doses can also increase insulin sensitivity, necessitating dose adjustments in diabetics on insulin or metformin. Combining NAD+ supplements with antioxidants like quercetin and resveratrol can raise NAD+ levels up to fivefold but also amplify side effects like hot flashes and nausea.

Bioavailability Variability: Individual responses to supplementation vary widely. Factors like age, baseline NAD+ levels, gut microbiome composition, CD38 activity, and genetic polymorphisms in NAMPT or NRK enzymes all influence efficacy. Blood NAD+ is an unreliable surrogate for tissue NAD+, and intracellular NAD+ testing—while available—is not yet standard practice.

Regulatory and Quality Issues: NMN's classification as a drug limits its market presence and may reduce product quality oversight in unregulated markets. Many commercial NAD+ supplements contain less than the labeled amount, and stability varies widely. NMN degrades rapidly when exposed to heat, moisture, and UV light, losing up to 30% potency within 48 hours under ambient conditions. NR is more chemically stable, making it easier to formulate and store.

Cost and Access: High-quality NAD+ supplements are expensive. A 30-day supply typically costs $80–$150, and IV NAD+ therapy ranges from $800 to $1,500 per session. This pricing structure risks creating a longevity divide, where only affluent individuals can access biochemical healthspan extension.

Global Perspectives: How Different Societies Approach NAD+ and Longevity

In Silicon Valley, NAD+ supplementation is part of a broader biohacking ethos that includes continuous glucose monitors, peptide injections, and hyperbaric oxygen therapy. Executives and entrepreneurs view aging as an engineering problem, and NAD+ boosters as a software update for cellular metabolism. This techno-optimist perspective has driven investment in longevity biotech, with companies like ChromaDex (which markets Niagen, a patented NR product) and MetroBiotech (focused on NMN analogues) raising hundreds of millions in funding.

In contrast, Japanese researchers have taken a more cautious, data-driven approach. Japan's Ministry of Health has approved multiple NMN clinical trials, and Japanese companies have pioneered high-purity NMN production. The emphasis is on rigorous safety testing and dose optimization rather than rapid commercialization. A 24-week trial in older diabetic Japanese men exemplifies this philosophy: modest doses (250 mg daily), careful monitoring, and transparent reporting of null results (no improvement in grip strength) alongside positive findings (reduced frailty prevalence).

European regulatory bodies have been more skeptical. The European Food Safety Authority (EFSA) has not granted NMN novel food status, limiting its sale across the EU. NR, having GRAS status in the U.S., has faced fewer barriers. This regulatory patchwork reflects differing risk tolerances: the U.S. prioritizes consumer access and market innovation, while Europe emphasizes precautionary regulation and long-term safety data.

In China, NMN has become a luxury wellness product, marketed to middle-aged professionals concerned about "overwork aging." E-commerce platforms sell NMN at premium prices, often without robust quality controls. This has led to concerns about counterfeit or contaminated products, underscoring the need for international regulatory harmonization.

Globally, the question is not whether NAD+ supplementation will become mainstream—it will—but whether access will be equitable, quality will be ensured, and long-term safety will be monitored. Public health agencies must balance innovation with consumer protection, ensuring that the NAD+ revolution benefits everyone, not just the wealthy and well-informed.

Preparing for the Future: Practical Guidelines for Safe, Effective Use

If you're considering NAD+ supplementation, here's how to do it intelligently:

Start Low, Go Slow: Begin with 250 mg of NR or NMN daily for two weeks. Monitor for side effects like nausea, headache, or digestive discomfort. If well tolerated, you can increase to 500 mg daily after two weeks, and to 1,000 mg if needed (though higher doses have not consistently shown additional benefit).

Choose Quality Products: Look for third-party testing (e.g., NSF, USP, ConsumerLab) and certificates of analysis confirming purity and potency. Prefer enteric-coated or liposomal formulations for better bioavailability. Avoid products that combine NAD+ precursors with unproven or untested ingredients.

Optimize Timing: Take NMN in the morning on an empty stomach (30 minutes before breakfast or 2 hours after a meal) to align with circadian NAD+ fluctuations and maximize absorption. NR can be taken with or without food, but morning dosing is generally preferred. Consider a hybrid sublingual-oral approach: dissolve half your dose under the tongue, swallow the rest.

Support Methylation: If taking high doses (≥500 mg daily), consider adding 200 mg of trimethylglycine (TMG) to replenish methyl donors. Some formulations include TMG, spermidine, and BioPerine (a black pepper extract that enhances absorption).

Combine with Lifestyle: NAD+ supplementation is not a substitute for exercise, sleep, and a balanced diet. Regular aerobic and resistance exercise upregulates NAMPT and sirtuins, amplifying the benefits of supplementation. Avoid high-fat, high-sugar diets, which lower NAD+ and impair mitochondrial function. Fermented foods (yogurt, kefir, kimchi) and heat exposure (sauna) can also boost NAD+ naturally.

Monitor Biomarkers: If possible, measure intracellular NAD+ levels before and after supplementation using commercially available tests (e.g., Jinfiniti's Intracellular NAD® Test). Track subjective markers like energy, sleep quality, and exercise recovery. Monitor blood pressure, fasting glucose, and inflammatory markers (CRP, IL-6) annually.

Avoid Drug Interactions: If you take warfarin, antihypertensives, insulin, or chemotherapy, consult your physician before starting NAD+ supplementation. Regular INR checks are essential if you're on anticoagulants.

Cycle or Plateau? Some experts recommend cycling NAD+ supplementation (e.g., 8 weeks on, 4 weeks off) to prevent NAMPT downregulation. Others suggest continuous use with periodic dose adjustments based on biomarker feedback. The optimal strategy remains unclear.

Be Realistic: NAD+ precursors are not a fountain of youth. They may improve metabolic health, reduce inflammation, and support mitochondrial function—but they won't make you 20 again. Expect subtle, incremental benefits that accrue over months to years, not dramatic overnight transformations.

The Bottom Line: NAD+ precursors offer a scientifically grounded, practical strategy for boosting cellular health without calorie restriction. They won't replace exercise or a healthy diet, but they can complement those efforts—especially for busy adults who can't fast for days or subsist on salads. The evidence is strongest for metabolic and cardiovascular benefits, with emerging signals for cognitive and anti-inflammatory effects. Safety data are reassuring in the short term, though long-term studies are still needed. Choose quality products, start with modest doses, and monitor your response. Most importantly, remember that healthspan extension is not a solo endeavor—it's a combination of biochemistry, behavior, and resilience. NAD+ precursors give you a biochemical edge, but how you live your life still matters most.

Welcome to the era of cellular hacking. Your mitochondria are waiting.

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