The COVID-19 pandemic resulted in an unprecedented global adoption of face masks. In 2020, approximately 77% of countries implemented mandatory mask policies, and an estimated 4.5 billion people—nearly 58% of the world population—were required to wear masks in public, including children in schools (1). This scale and duration of population-wide mask use is without historical precedent and has prompted renewed scientific interest in potential physiological consequences, including prolonged exposure to elevated inhaled carbon dioxide (CO₂).

Before the pandemic, several reports documented that certain mask types can increase inhaled CO₂ concentrations, occasionally approaching or exceeding occupational exposure limits for acute (3% for 15 min) or chronic (0.5% for 8 h) inhalation (2–6). Human physiological adaptation to increased CO₂ exposure involves acute ventilatory changes, with 1%−2% CO₂ inhalation inducing an approximately 34% rise in minute ventilation (7). When CO₂ accumulation surpasses compensatory capacity, respiratory acidosis may occur, triggering renal bicarbonate retention and increased H⁺ excretion to restore acid–base balance (8). Additional buffering adaptations—such as shifts in plasma electrolytes and bone-stored CO₂–have also been described (9, 10).

However, contemporary literature reveals conflicting findings regarding the physiological impact of mask-related CO₂ accumulation. While some experimental studies report measurable increases in breathing-zone CO₂, multiple systematic reviews—including an umbrella review published in 2025 (11) —have concluded that most mask types induce minimal to no clinically meaningful changes in respiratory rate, CO₂ retention, or cardiopulmonary burden in healthy adults. Such discrepancies highlight the methodological heterogeneity across studies, including differences in mask design, activity level, sensor placement, exposure duration, and participant characteristics (Figure 1).

Importantly, the capacity to compensate for CO₂-induced acid–base disturbances is not uniform across populations. Vulnerable groups—including older adults, children, pregnant women, and individuals with cardiopulmonary disease—may exhibit reduced ventilatory reserve and diminished physiological buffering (12, 13). This concern aligns with global public-health evidence showing that aging is associated with progressive loss of respiratory, renal, and metabolic resilience, as well as increased prevalence of multimorbidity and chronic inflammatory conditions that reduce homeostatic flexibility (Figure 1). Furthermore, contemporary gerontological reviews emphasize that aging populations experience disproportionate harm from environmental stressors, including heat, pollution, and air-quality fluctuations (14, 15). These insights are relevant when considering whether chronic, low-grade exposure to elevated CO₂ during prolonged mask use could act as an additional physiological stressor in older individuals.

Chronic or intermittent CO₂ exposure has been associated with cellular and molecular alterations, including inflammation, metabolic remodeling, disturbances in intracellular pH, and the formation of carboxylated protein derivatives (10) (Figure 1). Duarte et al. (16) hypothesized that persistent elevations in atmospheric or inhaled CO₂ may dysregulate the proteome via pH-dependent mechanisms, potentially influencing pathways involved in protein folding, aggregation, and interaction dynamics.

Protein misfolding and aggregation are well-established contributors to numerous age-related diseases (17). More than 20 amyloidogenic proteins associated with disorders such as Alzheimer's disease, Parkinson's disease, type 2 diabetes, and AA amyloidosis have been identified (18–20). Environmental factors—including pH, temperature, metal ions, and ionic strength—can lead to destabilization of native protein conformations, promoting fibrillogenesis (21, 22).

Given that amyloid-related diseases are strongly age-dependent and that the global population is rapidly aging—with older adults increasingly concentrated in institutional environments where mask use may be prolonged—the intersection between chronic CO₂ exposure, impaired proteostasis, and aging warrants careful examination. Recent public-health analyses confirm that older adults bear disproportionate morbidity from environmental exposures, including particulate pollution and climate-related stressors, underscoring the broader principle that age-related fragility magnifies the effects of otherwise modest physiological challenges.

This review highlights the complex interplay between CO₂-related physiological changes, pH-dependent protein misfolding, and the age-related decline of proteostasis. While current evidence indicates that mask-associated CO₂ exposure produces only small changes in arterial pH in healthy adults, aging markedly reduces ventilatory reserve, buffering capacity, mitochondrial resilience, and the functionality of chaperone-mediated and autophagic quality-control pathways. These age-related vulnerabilities may lower the threshold at which otherwise minor physiological stressors—including small pH fluctuations—become biologically meaningful. Given the accelerating demographic shift toward aging societies, understanding how chronic low-grade acidosis, impaired proteostasis, and environmental stressors interact to influence amyloidogenic risk is increasingly important for public-health planning.

This narrative review therefore explores the theoretical relationship between prolonged mask use, CO₂-mediated pH alterations in biological fluids, and the molecular pathways of amyloidogenesis. We integrate (i) respiratory physiology under mask-related hypercapnia, (ii) pH-dependent mechanisms of protein misfolding, and (iii) population-specific vulnerabilities, with particular focus on older adults. The mechanistic connection between mild chronic hypercapnia and amyloid formation remains hypothetical; the aim of this review is not to claim causality but to evaluate whether available biochemical and epidemiological evidence justifies further investigation into chronic CO₂ exposure as a potential modulator of proteostasis in aging populations.

Mask-induced airway resistance and CO₂ rebreathing were experienced globally during the COVID-19 pandemic for more than 12 months, resulting in daily CO₂ exposures that frequently exceeded short-term recommended limits. Consequently, the potential implications of long-term exceedance of safe exposure thresholds require careful evaluation. Fresh ambient air contains approximately 0.04% CO₂, whereas wearing masks for more than 5 min has been shown to result in chronic exposure to inhaled CO₂ concentrations ranging from approximately 1.41%−3.2% (13). When the mouth and nose are covered, the fraction of re-inhaled air increases, and CO₂ concentrations may exceed 3%, while oxygen levels may decrease to around 17% (23), as summarized in a recent review detailing CO₂ rebreathing associated with mask use (13).

There is accumulating evidence that mask wearing correlates with increases in blood CO₂ levels, resulting in slight reductions in blood pH and mild acidosis. However, existing studies differ markedly in methodology, including mask type [surgical mask (SM), filtering face piece (FFP2), N95], duration of exposure (short-term vs. prolonged), sampling site (arterial vs. capillary blood), analytical protocols, and the physical activity performed during mask use (ranging from routine work in healthcare settings to controlled light or intense exercise across varying age groups and sexes). These methodological differences complicate direct comparisons across studies.

While some studies report measurable increases in CO₂ microenvironment concentrations, convergent evidence from systematic reviews indicates that these elevations largely remain within compensatory capacity in healthy adults, highlighting the need for standardized measurement frameworks. To minimize bias, both supportive and non-supportive evidence must be considered, highlighting the need for standardized, long-duration CO₂ monitoring protocols. The physiological significance of mask-related CO₂ elevation therefore remains a subject of ongoing debate.

Grimm et al. (24) investigated 23 healthy volunteers and reported that both surgical mask (SM) and filtering facepiece class 2 (FFP2) masks significantly increased capillary blood pCO₂ (SM: 35.2 ± 4.0 mmHg; FFP2: 34.5 ± 3.8 mmHg; F = 12.670, p < 0.001) and decreased capillary blood pH (SM: 7.39 ± 0.03 mmHg; FFP2: 7.39 ± 0.04 mmHg; F = 11.4, p < 0.001) during exercise compared to no-mask conditions (pCO₂: 31.9 ± 3.3 mmHg; pH: 7.42 ± 0.03). The authors further noted that CO₂ generation during intense short-term activity increased, while CO₂ elimination was reduced when masks were worn, resulting in measurable disturbances of acid–base homeostasis and slight acidosis.

Long-term effects of mask use on blood gases were examined by Decha and Sonthaya (25) in 50 healthy adults performing running exercises while wearing reusable masks. Their findings demonstrated significant increases in arterial and red blood cell CO₂ levels during mask use (p < 0.05). CO₂ levels in the vigorous exercise group were significantly higher than in the moderate exercise group (p < 0.01). Despite these changes, arterial blood pH did not differ significantly before and after mask use (p > 0.05).

Several systematic reviews and controlled studies conclude that although mask use increases inhaled and exhaled CO₂ concentrations, the resulting systemic CO₂ levels in healthy individuals generally remain below National Institute for Occupational Safety and Health (NIOSH) limits for acute and chronic exposure, and do not induce clinically meaningful hypercapnia (4, 26) (Figure 2).

Recent work by Bao et al. (12), involving 30 healthy volunteers, evaluated the short-term physiological effects of wearing N95 masks during light and heavy exercise. The authors observed a reduction in venous pH, and calculated arterial pH demonstrated a downward trend following a 14-h masked intervention.

Conversely, Cebecioglu et al. (27) assessed respiratory function in 60 healthcare workers wearing surgical masks during the COVID-19 pandemic and reported no significant differences in venous blood pH, pO₂, or pCO₂ following at least 8 h of mask use. Venous blood samples collected before and after the work shift demonstrated stable values for pH, SpO₂, PaO₂, PaCO₂, HCO3−, lactate, base excess, and oxygen saturation.

Ipek et al. (28) examined 34 healthcare workers who wore a surgical mask on the first day and an N95 mask on the following day for 1–4 h. Capillary blood gases obtained after mask removal revealed significantly higher pH values following N95 use (7.48 ± 0.04) compared to surgical mask use (7.43 ± 0.03) (p < 0.001). pCO₂ levels were significantly lower after N95 use (28.46 ± 7.77 mmHg) than after surgical mask use (37.33 ± 8.81 mmHg) (p < 0.001). HCO3− levels did not differ significantly between conditions (p = 0.113).

Tărăboanţă et al. (29) evaluated salivary parameters in 40 healthy participants after 2 h of wearing surgical and FFP2 masks. Measurements of unstimulated and stimulated salivary flow rate, pH, and buffer capacity taken on a non-mask day and after mask use revealed no statistically significant differences in salivary pH. To date, no data exists on long-term mask use and salivary pH.

The tear film protects the ocular surface by maintaining physiological pH (7.14–7.82), osmolarity, and electrolyte composition, with a secretion rate of approximately 2 μl/min ensuring continuous turnover (30). Exhaled air contains reduced oxygen and elevated CO₂ levels, which can decrease tear film pH and potentially compromise ocular surface integrity (31). Corneal polymodal nociceptors—responsive to mechanical, thermal, and chemical stimuli—are activated by acidic solutions, with impulse frequency proportional to decreasing extracellular pH (32). Exposure of the ocular surface to CO₂-rich air decreases corneal pH, thereby activating these nociceptors (33). During mask use, upward leakage of exhaled air with elevated CO₂ content decreases tear film pH (30), impairs ocular surface homeostasis (31), and reduces stromal pH (34), collectively contributing to corneal pain sensations (35).

While ocular surface acidification provides a clear example of CO₂ related pH reduction in a localized microenvironment, systemic acid–base regulation operates under different compensatory constraints, particularly in aging adults.

The body maintains acid–base homeostasis through coordinated regulation by the lungs, kidneys, and serum buffering systems. Tissue acidosis may arise from increased CO₂ accumulation or from excess production or inadequate clearance of metabolic acids (36). Respiratory acidosis (pH < 7.35) develops (Figure 3) when CO₂ production exceeds the capacity of the lungs to eliminate it (37). It is defined by elevated arterial CO₂ tension (PaCO₂ > 45 mmHg) resulting from alveolar hypoventilation (primary hypercapnia) (38). Respiratory acidosis may be acute, with bicarbonate (HCO3−) increasing only 1 mEq/L for every 10 mmHg rise in PaCO₂, or chronic (duration > 24 h), when renal compensation increases HCO3− by approximately 4 mEq/L for every 10 mmHg rise in PaCO₂ (39).

Metabolic acidosis (Figure 3) is typically a chronic condition characterized by retention of acid and depletion of bicarbonate stores, primarily affecting intracellular and interstitial compartments. Diagnosis requires assessment of fasting serum bicarbonate, urinary pH obtained ≥4 h after the last meal, and 24-h urinary citrate (40). Low-grade metabolic acidosis reduces systemic buffering capacity, increasing reliance on bone, muscle, and connective tissue to neutralize acid loads. This condition becomes more harmful with aging (Figure 3), as reduced renal function and diminished adaptive capacity impair the ability to maintain acid–base equilibrium. Even mild acidosis promotes urinary losses of sodium and potassium and accelerates bone demineralization by increasing osteoclast activity and reducing osteoblast function, thereby elevating the risk of osteoporosis and kidney stone formation.

Some individuals retain a normal systemic pH (7.35–7.45) despite deficiencies in buffering systems. Nevertheless, elevated intracellular and interstitial acidity may induce cellular injury, nociceptive signaling, and insulin resistance (41). Serum bicarbonate ≤24 mEq/L supports the diagnosis of low-grade metabolic acidosis, especially when associated with low urinary citrate or elevated urinary ammonium (42). Urinary pH values <5.3 in adults and <5.6 in children indicate metabolic acidosis (43).

In healthy tissues, extracellular pH averages ~7.4. However, interstitial acidification (pH < 6.5) is observed in inflammatory states, including solid tumors and infections (44). Intracellular pH is regulated through multiple buffering systems, such as Na⁺/H⁺ exchangers, Na⁺-driven HCO3− transporters, Cl⁻/HCO3− exchangers, and ATP-dependent H⁺ pumps (45). Chronic extracellular acidosis disrupts cellular homeostasis, metabolism, signaling pathways, and gene transcription (46).

Acidosis (Figure 3) has been associated with ischemia, neuronal degeneration, chronic pain, and seizures (47). Acid-sensing ion channels (ASICs)—sodium- or calcium-permeable channels composed of three subunits (48)—are implicated in multiple neurological disorders, including Parkinson's disease, Huntington's disease, glioma, and seizure disorders (49). Hypoxia reduces pH and increases inflammatory mediators such as nitric oxide, arachidonic acid, and IL-1, all of which can activate or upregulate ASICs (49). Severe acidosis induces neuronal atrophy and membrane rupture, promoting rapid cell death. This leads to uncontrolled release of amyloid-β (Aβ), contributing to extracellular aggregation, plaque formation, and potential initiation of the Aβ cascade (50).

Acidosis may also contribute to the pathogenesis of vascular dementia and Alzheimer's disease (AD) (Figure 3). Low pH facilitates iron-catalyzed formation of reactive oxygen species by releasing iron from transferrin, ferritin, and other storage proteins (51). In vivo studies in 34 older adults demonstrated pH reductions in brain tissue using magnetic resonance spectroscopic imaging (52). Extracellular acidosis has also been detected in cerebrospinal fluid (53) and postmortem AD brain tissue (54). Blood acidification is a recognized feature of normal aging (55) and may reflect a broader age-related physiological process of declining acid–base resilience. Collectively, these findings suggest that brain acidification may represent a global phenomenon that worsens with advancing age, contributing to neurodegenerative vulnerability in older populations.

Acidosis may also intersect with diabetes-related pathways that accelerate AD onset and progression (Figure 3). Degradation of Aβ by insulin-degrading enzyme (IDE) is reduced at low pH (56). Additionally, both acute and chronic hypoglycemia cause neuronal injury through excessive glutamate and aspartate release, triggering calcium influx and decreasing intracellular pH (51).

Finally, excess human islet amyloid polypeptide (IAPP) represents a major pathological contributor to diabetic encephalopathy (DE). In patients with type 2 diabetes mellitus (T2DM), serum IAPP levels correlate positively with white-matter injury and negatively with cognitive performance. In vitro studies reveal that oligodendrocytes are more susceptible than neurons to acidosis induced by exogenous IAPP (57), underscoring a mechanistic link between metabolic dysregulation, acidification, and accelerated neurodegeneration in aging populations.

Aging is accompanied by progressive physiological changes in the respiratory system (Figure 4) that diminish ventilatory reserve and reduce the capacity to maintain gas-exchange homeostasis under stress. These age-associated alterations affect multiple components of respiratory function, including chemosensitivity to CO₂, the mechanical properties of the thoracic cage, alveolar–capillary diffusion efficiency, and renal acid–base compensatory mechanisms (Figure 4).

The age-related decline in respiratory, metabolic, and proteostatic resilience described here is reflected at the population level. Epidemiological analyses show that disability and chronic disease now account for the majority of years lived after age 60, and that age-structure effects alone explain nearly all projected increases in DALYs (58). Thus, the mechanistic vulnerabilities outlined in this work align with observed trajectories of functional decline in aging populations.

Protein misfolding is driven by physicochemical stressors—including altered temperature, pH, protein concentration, and oxidative conditions—that destabilize native conformations and expose hydrophobic surfaces, promoting aggregation and precipitation (83) (Figure 5). Environmental factors such as pollutants and smoking can induce structural modifications, while genetic contributors include pathogenic mutations, errors in transcription or translation, impaired chaperone function, and defective post-translational processing. Aggregation propensity is additionally modulated by pH, protein concentration, and the presence of metal ions such as copper and zinc, which may accelerate or inhibit fibrillization depending on their concentration, coordination chemistry, and surrounding biochemical environment (83).

Experimental evidence shows that pH-dependent amyloidogenesis requires substantially larger acidification than occurs physiologically during mask-related CO₂ exposure (Figure 5). Studies across multiple amyloid systems demonstrate that amyloidogenic proteins—including Aβ, IAPP, and β₂-microglobulin—undergo conformational shifts, accelerated nucleation, or fibrillization primarily under moderate to strongly acidic conditions, requiring pH reductions of approximately 0.3–1.5 units. For example, Aβ primary nucleation accelerates as pH approaches its pKa near 7.0, with aggregation markedly faster at pH 6.0–7.0, while Aβ1-40 undergoes an unfolded, aggregation-prone conformation at pH ≈ 4. Similarly, Aβ16–22 peptides adopt extended β-strand fibril structures at acidic pH, promoting macroscopic assembly, and β₂-microglobulin fibril–membrane disruption is strongly enhanced under acidic conditions, consistent with an acid-dependent shift in amyloidogenic behavior. By contrast, physiological evidence indicates that mask-associated CO₂ retention produces only minimal arterial pH changes—typically 0.01–0.05 units in healthy individuals, because respiratory and renal homeostatic systems maintain blood pH tightly within 7.35–7.45 even during mild hypercapnia. These CO₂-induced pH shifts are therefore one to two orders of magnitude smaller than experimentally induced acidifications used to trigger amyloidogenesis. Consequently, mask-related CO₂ exposure alone is highly unlikely to reach amyloid-triggering thresholds, although individuals with modifying vulnerabilities—including chronic inflammation, which can acidify microenvironments and accelerate Aβ assembly, renal disease, which increases β₂-microglobulin accumulation and promotes amyloidogenesis, or impaired proteostasis or genetic factors, which lower the threshold for misfolding stress—may exhibit a reduced margin of physiological protection (59–61, 64, 84, 85).

Amyloid fibril formation is a nucleation-dependent polymerization process in which hundreds to thousands of monomeric peptides assemble into elongated β-sheet-rich fibers (22). It proceeds through a slow primary nucleation lag phase, during which small, unstable oligomeric nuclei form, followed by rapid elongation, where monomers add to growing fibrils, and a final plateau once saturation is reached (Figure 5). Many proteins first convert into partially folded, aggregation-prone intermediates, allowing assembly without full unfolding; these intermediates can act as new nuclei that accelerate fibril growth (86). In an alternative secondary-nucleation model, fragmentation of existing fibrils generates additional growth points, markedly enhancing fibrillization (87). Both mechanisms are highly sensitive to environmental parameters, including pH, which can significantly accelerate aggregation. Importantly, growing evidence indicates that soluble prefibrillar oligomers, rather than mature fibrils, are the most cytotoxic species in amyloid diseases, as demonstrated for Aβ (88), tau fragments, huntingtin exon 1, and IAPP.

Older adults have a higher prevalence of chronic conditions—chronic obstructive pulmonary disease (COPD), chronic kidney disease (CKD), diabetes, neurodegenerative disorders—that already compromise pH homeostasis and involve endogenous amyloidogenic proteins (Aβ, IAPP, β₂-microglobulin). Even small additional acid-base stressors may therefore exacerbate ongoing misfolding pathways.

Amyloidosis presents with highly variable and often subtle symptoms, reflecting the specific organs in which amyloid accumulates. As deposits enlarge, they disrupt tissue architecture and function, producing a clinical spectrum ranging from mild, non-specific complaints to severe, life-threatening organ failure (102). Prognosis depends on amyloid type, organ involvement, and response to therapy; untreated systemic forms are typically fatal. Chronic inflammatory disease is a major driver of amyloid A (AA) amyloidosis, and delayed or missed diagnosis worsens outcomes. Cardiac infiltration markedly increases mortality, whereas gastrointestinal involvement—while less lethal—can cause nausea, diarrhea, or constipation.

pH-dependent aggregation of misfolded peptides and proteins is well documented in Alzheimer's disease, Parkinson's disease, and related neurodegenerative conditions (103). These observations underscore the need to better understand how changes in local acidity and immune activation may promote amyloidogenesis in other disorders, including ocular diseases such as cataract.

Contemporary classification of amyloidosis emphasizes the biochemical nature of the precursor protein. The most common systemic forms include amyloid light chain (AL) amyloidosis, caused by monoclonal light chains from clonal plasma-cell or B-cell disorders; AA amyloidosis, a complication of sustained elevation of serum amyloid A during chronic inflammation, leading to extracellular fibril deposition and progressive organ damage (104); and hereditary transthyretin amyloidosis (ATTR), an autosomal-dominant condition involving >130 transthyretin mutations, characterized by variable penetrance and severe cardiac and neurologic involvement (105).

These diverse forms of amyloidosis highlight how biochemical instability, inflammatory environments, and genetic predisposition interact to drive pathogenic fibril formation and organ dysfunction.

AL amyloidosis arises from misfolded immunoglobulin light chains that deposit in organs, causing progressive tissue damage and organ dysfunction. Kidney involvement occurs in roughly two-thirds of patients and frequently leads to renal failure, edema, and fatigue. Cardiac infiltration produces restrictive cardiomyopathy with dyspnea, arrhythmias, and high mortality. Recent in vitro work shows that AL fibrillogenesis begins with partial unfolding of the VL domain, dimer formation, and oligomerization through a multi-step β-sheet transition pathway (106). Aging increases susceptibility to AL disease by weakening proteostasis capacity and increasing systemic inflammation, both of which amplify light-chain misfolding risk.

AA amyloidosis results from chronic overproduction of serum amyloid A (SAA), typically driven by long-standing inflammatory disorders (107). SAA converts into extracellular amyloid fibrils that predominantly damage the kidney but may also involve the liver, spleen, thyroid, and bowel (108). SAA is intrinsically disordered; at acidic pH (3.5–4.5) it forms α-helical oligomers that convert into β-sheet structures on lipid membranes, suggesting a pH-dependent membranolytic mechanism (109). Aging—characterized by chronic low-grade inflammation (inflammaging) and impaired lysosomal clearance—further increases the likelihood of persistent SAA elevation and amyloid deposition.

ATTR amyloidosis is caused by >130 pathogenic TTR mutations leading to destabilized tetramers that misfold and aggregate extracellularly (105). Clinical manifestations include progressive peripheral neuropathy, autonomic dysfunction, and cardiomyopathy (110). Low-pH models show that acidic environments facilitate TTR tetramer dissociation and partial unfolding, accelerating fibrillization. Although stabilizing drugs like tafamidis improve TTR stability, they do not fully halt progression. Age further increases TTR amyloid risk due to declining proteostasis and reduced chaperone capacity, helping explain the strong association between ATTR and advanced age. LECT2 amyloidosis is now recognized as a major cause of renal amyloid deposition. LECT2 fibrillization requires loss of its bound Zn(II); zinc occupancy is strongly pH-dependent, dropping to ~20% at pH 6.5 (111). Aging-related changes in metal homeostasis and acidic microenvironments—common in chronic kidney disease—may therefore facilitate LECT2 dissociation and aggregation.

Mutations in the A-chain promote renal-dominant amyloid deposition, leading to proteinuria, hypertension, and azotemia, with occasional multiorgan involvement. Several TTR and A-chain mutants show markedly enhanced amyloid formation at moderately acidic pH, supporting a shared mechanism of pH-triggered destabilization and aggregation (112).

Cataract formation—responsible for most age-related blindness—results from aggregation of α-, β-, and γ-crystallins in the lens, a tissue that lacks protein turnover. Age-dependent covalent modifications, including deamidation, oxidation, and truncation, promote crystallin aggregation. pH-dependent destabilization also contributes: the βB1 R233H mutation, benign at neutral pH, significantly increases aggregation at acidic pH, implicating protonation-dependent destabilization (113). Such pH sensitivity aligns with the general decline of proteostasis and buffering capacity during aging.

Aging consistently amplifies susceptibility to systemic amyloidoses—including AL, AA, ATTR, ALECT2, hereditary forms—and to age-related protein-aggregation diseases such as cataract. Across these conditions, advancing age contributes to a progressive collapse of proteostasis, marked by declining chaperone activity, impaired proteasomal degradation, and reduced autophagy–lysosomal clearance, all of which heighten the cellular burden of misfolded or aggregation-prone proteins. Aging is also characterized by chronic low-grade inflammation, which elevates circulating SAA and immunoglobulin light chains, thereby increasing the substrate load for AA and AL amyloid formation. Concurrent decline in renal function reduces systemic buffering and accelerates acidotic microenvironments, conditions that promote amyloidogenic folding and worsen outcomes in AL and AA amyloidosis. Age-dependent metal dyshomeostasis, combined with localized pH shifts, further destabilizes protein structures and facilitates aggregation pathways implicated in neurodegeneration and crystallin aggregation in cataract. Compounding these effects, aging reduces the fidelity of protein-folding quality control, increasing proteome-wide insolubility and enhancing vulnerability to amyloid deposition across multiple organ systems. Collectively, these aging-related biological changes lower the threshold for amyloid formation and accelerate disease progression across diverse amyloid disorders.

Over the past two decades, major advances have transformed the early diagnosis of neurodegenerative disorders. Modern approaches now combine structural and functional neuroimaging, positron emission tomography (PET), biomarker-based assays, genetic sequencing, and digital physiological monitoring to improve diagnostic accuracy (114). Fluid-based biomarkers from cerebrospinal fluid, blood, serum, or saliva provide a less invasive and more cost-effective alternative to PET imaging for detecting molecular hallmarks of disease (115). In amyloidosis, the defining diagnostic signature is the cross-β fibrillar architecture, whose highly ordered, repetitive, and rigid structure allows detection through both in vivo and in vitro analytical techniques. Accurate diagnosis, classification, and staging require clinical assessment supported by electrocardiography and Doppler studies for cardiac involvement, manometry and gastric emptying tests for gastrointestinal dysfunction, and targeted blood or urine biomarkers. Ultimately, amyloid typing relies on tissue biopsy analyzed by immunohistochemistry or immunofluorescence, complemented by advanced structural methods such as solid-state NMR and cryo-TEM for fibril characterization.

This narrative review synthesizes mechanistic, physiological, and public-health evidence to examine how chronic or intermittent exposure to mildly elevated CO₂–such as may occur during prolonged mask use—interacts with aging-related declines in respiratory, metabolic, and proteostatic resilience. Current data indicate that mask-associated CO₂ elevations in healthy adults generally remain within the range of physiological compensation and produce only minimal changes in arterial pH. These shifts are far smaller than those required experimentally to accelerate amyloid fibrillogenesis. Nonetheless, aging fundamentally reshapes the body's capacity to respond to metabolic and physicochemical stressors, narrowing homeostatic reserve across multiple systems. Declines in ventilatory responsiveness, renal buffering, mitochondrial efficiency, muscle-based metabolic support, and proteostasis collectively heighten vulnerability to even modest perturbations in pH, CO₂, and oxidative or inflammatory load.

Across the lifespan, amyloidogenic proteins remain sensitive to acid–base conditions, metal dyshomeostasis, and proteostatic imbalance. While mild hypercapnia alone is unlikely to trigger amyloid formation, the cumulative interplay of chronic disease, inflammation, impaired clearance pathways, and aging-associated acidification may lower the threshold at which misfolding and aggregation become pathophysiologically relevant. This is particularly important given demographic trends toward rapidly aging populations, rising prevalence of chronic kidney disease, diabetes, and neurodegenerative disorders, and increasing numbers of older adults living in institutional environments where prolonged mask use may be routine.

From a public-health perspective, these findings underscore the need for age-stratified risk–benefit analyses when considering long-duration mask policies, personal protective equipment (PPE) design, and ventilation standards. They also highlight broader principles: aging increases exposure to physiological stressors while simultaneously diminishing resilience to them. As such, subtle environmental or metabolic challenges that are benign in younger adults may exert amplified biological effects in older individuals.

Clarifying the long-term implications of repeated low-grade hypercapnia, chronic acidosis, and impaired proteostasis requires rigorous, longitudinal, and mechanistically integrated research. Future studies should prioritize older adults and individuals with reduced ventilatory or renal reserve, incorporate standardized CO₂ and pH monitoring protocols, and evaluate biomarkers of proteotoxic stress, inflammation, and metabolic compensation. Understanding how these factors intersect will be essential for guiding public-health strategies, optimizing protective equipment for high-risk groups, and ultimately safeguarding healthspan in aging societies.

Several limitations must be acknowledged. First, available studies on mask-induced CO₂ retention are heterogeneous in design, mask type, exposure duration, sampling methodology, and participant age, limiting direct comparability. Conflicting findings—ranging from measurable hypercapnic responses to no detectable systemic change—reflect inconsistencies in study protocols and measurement technologies. Second, most mechanistic insights into amyloidogenesis and pH-dependent protein misfolding derive from in vitro systems operating at far more acidic conditions than occur physiologically, making translational interpretation challenging. Third, data on older adults, individuals with chronic disease, and long-term mask users remain sparse. Finally, the speculative nature of linking chronic, mild hypercapnia to misfolding pathophysiology underscores the need for rigorous, longitudinal, and age-stratified research before drawing causal inferences.

Future work should prioritize longitudinal and stratified clinical studies to evaluate CO₂ retention, acid–base status, and proteostasis markers specifically in older adults, individuals with impaired renal or respiratory function, and those with chronic inflammatory or neurodegenerative conditions. Standardized protocols for measuring CO₂ microenvironment levels, arterial and tissue pH, and biomarkers of proteotoxic stress are needed to reconcile existing discrepancies in the literature. Parallel experimental studies should investigate how mild, chronic acidosis affects aggregation kinetics of endogenous amyloidogenic proteins in physiologically relevant conditions and aging cellular models. Integration of multi-omics approaches—proteomics, metabolomics, and metallomics—may elucidate how aging-related changes in metal homeostasis, mitochondrial function, and protein-folding networks modulate susceptibility to misfolding.

At the population level, future research should evaluate risk-benefit frameworks for prolonged mask use in older adults and medically vulnerable groups. This includes studying the effects of mask design, fit optimization, ventilatory ergonomics, and structured break protocols on physiological outcomes. Public-health strategies may also benefit from the development of age-specific guidelines that incorporate physiological reserve, multimorbidity profiles, and proteostasis capacity.

Understanding how environmental stressors interact with aging physiology offers an important opportunity to refine preventive strategies for amyloidosis-related and other protein-misfolding disorders. As societies age, the identification of early biomarkers, individualized risk assessment, and tailored public-health recommendations will be essential for maintaining healthspan and mitigating long-term disease burden.