Hormesis

Box breathing is a paced breathing technique using equal-length phases of inhale, hold, exhale, and hold (commonly four seconds each). Slowing respiration well below the typical 12–16 breaths per minute is associated with increased vagal tone and heart-rate variability in slow- and resonance-breathing studies. It is widely taught in military, clinical, and performance settings for acute stress regulation. Direct RCT evidence for box breathing as a distinct protocol is limited; most support is extrapolated from broader paced/slow-breathing research.

Cold exposure is the deliberate use of cold air, water, or ice (cold showers, ice baths, cryotherapy) as a hormetic stressor. Acute cold triggers noradrenaline release and peripheral vasoconstriction and, if sufficiently intense, shivering thermogenesis; some protocols are non-shivering by design. It may activate brown adipose tissue, though BAT activation in humans varies substantially with the exposure protocol and detection method. Reported effects include improved cold tolerance and subjective alertness; evidence for metabolic, immune, and longevity benefits in humans remains limited and mixed.

Cold thermogenesis is the body's heat-producing response to cold, comprising shivering thermogenesis in skeletal muscle and non-shivering thermogenesis driven by UCP1-dependent activation of brown and other thermogenic ('beige') adipose depots. Repeated cold stimulation can increase tracer-based glucose uptake by thermogenic adipose tissue in small imaging studies, though this reflects local activity rather than necessarily systemic metabolic improvement. Whether these effects translate into durable, clinically meaningful improvements in body composition or metabolic health remains under investigation.

The heat shock response is a conserved cellular program triggered by elevated temperature and other proteotoxic stressors. Heat shock factor 1 (HSF1) activates transcription of heat shock proteins (HSPs) such as HSP70 and HSP90, which act as chaperones to refold or degrade damaged proteins. This pathway supports proteostasis and is hypothesised to mediate hormetic benefits of sauna and exercise; direct human longevity evidence remains preliminary.

Hyperbaric oxygen therapy delivers 100% oxygen at pressures typically of 2.0–2.4 atmospheres absolute (with the clinical threshold for HBOT generally defined as at least 1.4 ATA) inside a pressurised chamber, dramatically increasing dissolved oxygen in plasma. It is an established treatment for decompression sickness, carbon monoxide poisoning, and selected non-healing wounds. Off-label longevity uses (telomere length, cognition, anti-ageing) rely on small trials with methodological limits; current evidence does not support routine use for healthy ageing.

Hypoxia training exposes the body to reduced oxygen, either continuously (altitude, hypoxic tents) or intermittently (cycles of low and normal oxygen). Reported adaptations include stabilisation of hypoxia-inducible factor (HIF), and the practice may increase EPO/erythropoiesis and has been associated with mitochondrial adaptations, though magnitude depends strongly on hypoxic dose, duration, and individual factors. Used by endurance athletes and studied for cardiometabolic and cognitive applications, the evidence is heterogeneous, and intermittent hypoxia carries risks particularly in obstructive sleep apnea or certain cardiovascular conditions.

Ischemic preconditioning (IPC) is a hormetic phenomenon in which brief, sublethal cycles of tissue oxygen deprivation followed by reperfusion protect against a subsequent lethal ischemic event. Murry, Jennings, and Reimer (1986) showed four 5-minute coronary occlusions in dogs reduced infarct size by ~75%. Two protection windows operate: an early phase (1–3 h) driven by adenosine receptors, protein kinase C (PKC), and ATP-sensitive potassium channels (K_ATP); and a late phase (12–24 h) requiring de novo synthesis of heat-shock protein 70 and inducible nitric oxide synthase. Both converge on inhibition of the mitochondrial permeability transition pore (mPTP), preventing the membrane permeabilization that kills cardiomyocytes at reperfusion. Remote IPC (RIPC), induced by limb cuff inflation, transmits protection via humoral mediators (nitrite, SDF-1, micro-RNAs) and autonomic pathways. Aging blunts PKC signalling and K_ATP responsiveness — a deficit caloric restriction and exercise can partly reverse. Despite consistent animal data, two large randomised trials (ERICCA n≈1,600; RIPHeart n≈1,400; 2015) found no benefit after cardiac surgery under propofol, implicating anaesthetic interference. RIPC for stroke prevention or broader organ protection remains investigational.

Mitohormesis is the phenomenon by which transient, low-to-moderate increases in mitochondrially generated reactive oxygen species (ROS — superoxide, hydrogen peroxide, and related radicals) trigger protective adaptive responses improving cellular stress resistance, metabolic health, and longevity. These ROS pulses act as intracellular signals, activating transcription factors including NRF2 and p38 MAPK, upregulating antioxidant enzymes (superoxide dismutase, catalase, glutathione peroxidase) and inducing mitophagy. This dose-dependent, bell-shaped response was formalized by Ristow and colleagues through C. elegans and human studies linking exercise and caloric restriction benefits to ROS-dependent signaling. A 2009 PNAS trial (Ristow et al.) showed that vitamin C (1,000 mg/day) and vitamin E (400 IU/day) taken during a 4-week exercise program abolished improvements in insulin sensitivity and antioxidant defenses, implicating ROS as necessary adaptive signals. In aging, mitohormetic signaling declines alongside mitochondrial biogenesis, contributing to sarcopenia and metabolic deterioration; structured exercise — endurance and resistance training in particular — remains the best-evidenced intervention in humans, while pharmacological ROS mimetics remain investigational.

Photobiomodulation, often called red light therapy, applies low-level red and near-infrared light to tissue; most clinical devices use ~600–900 nm, with some PBM literature extending toward ~1100 nm. The proposed mechanism likely involves multiple pathways, including absorption by cytochrome c oxidase in mitochondria, nitric oxide signalling, and broader mitochondrial redox modulation, which together influence ATP production and reactive oxygen species. Clinical evidence supports modest benefits for some skin and musculoskeletal conditions; broader anti-ageing, cognitive, or metabolic claims rest on small or preliminary trials and are not yet established.

Pulsed electromagnetic field therapy delivers low-frequency, low-intensity pulsed magnetic fields to tissue, typically via flat coil applicators at frequencies from 1 to several hundred Hz and field strengths far below therapeutic MRI levels. Proposed mechanisms include voltage-gated ion channel modulation (particularly calcium influx), mitochondrial membrane potential effects, and downstream shifts in reactive oxygen species and inflammatory signaling, though the biophysical mechanisms remain incompletely characterised. Regulatory approval exists for specific indications—bone non-union healing and post-operative pain in some jurisdictions—supported by a moderate body of evidence. Evidence for broader longevity, metabolic, cognitive, or recovery applications is heterogeneous: some small RCTs report reductions in pain and inflammation, but effect sizes are variable, blinding is difficult, device parameters differ widely across studies, and high-quality long-term human trials are lacking.

A Finnish sauna is a dry-heat bath, typically 80–100°C with low humidity, used as a passive heat-stress modality. Acute sessions raise core temperature and produce a cardiovascular response (e.g. increased heart rate and peripheral vasodilation) that overlaps with some aspects of exercise, but is not equivalent to aerobic training. Large Finnish cohort studies, often categorising sessions as 1, 2–3, and 4–7 per week, link frequent use with lower cardiovascular and all-cause mortality, with the lowest risk in the 4–7 group; data are observational and causal effects on longevity are not established.

Whole-body cryotherapy (WBC) exposes the body to extreme cold air, typically −100 to −140°C, for 2–4 minutes inside a nitrogen-vapour or electric cryo-chamber, in contrast to cold-water immersion (CWI) at approximately 10–15°C for 10–15 minutes; the two modalities differ substantially in cooling rate, depth of tissue cooling, and physiological response. Proposed mechanisms include acute noradrenaline and endorphin release, transient anti-inflammatory cytokine shifts, and sympathoadrenal activation followed by a parasympathetic rebound. A 2015 Cochrane review (Costello et al., CD010789) found insufficient evidence to determine whether WBC reduces muscle soreness or improves recovery compared with passive rest, rating evidence quality as low to very low; evidence for immune, metabolic, or longevity-specific effects in healthy adults is preliminary. WBC carries risks of frostbite, hypoxia from nitrogen vapour, and cardiovascular stress, and is contraindicated in cold urticaria, Raynaud's phenomenon, and severe cardiovascular disease.

The Wim Hof method combines cyclic hyperventilation-style breathing, breath holds, and gradual cold exposure, popularised by Dutch athlete Wim Hof. Small studies report transient effects on sympathetic activation, catecholamine release, and short-term immune markers after lipopolysaccharide challenge. Long-term and clinical benefits, including for chronic disease or longevity, remain unproven, and the breath-hold component carries risks of fainting, especially in or near water.

Xenohormesis is the hypothesis that animals benefit from stress-response molecules produced by stressed plants and microbes, sensing them as cues of environmental adversity. Polyphenols such as resveratrol, quercetin, and curcumin are typical examples, proposed to activate sirtuins, AMPK, and other stress-defence pathways, although direct sirtuin activation by resveratrol has been disputed, with much of the in-vivo effect now attributed to AMPK and indirect pathways. Direct evidence that dietary xenohormetic compounds extend human healthspan is still limited.