1. TFEB and the Lysosomal Adaptation

Transcription factor EB (TFEB) belongs to the microphthalmia/transcription factor E (MiT/TFE) transcription factor family, which also includes transcription factor E3 (TFE3), microphthalmia-associated transcription factor (MITF), and transcription factor EC (TFEC)^[1]. Among these, TFE3 shares overlapping regulatory mechanisms and target genes with TFEB, including binding to coordinated lysosomal expression and regulation (CLEAR) elements, and can partially compensate for TFEB activity in certain stress contexts^[2,3].

TFEB serves as the master regulator of the CLEAR gene network^[4,5]. Through this program, TFEB controls lysosomal biogenesis and lysosome-dependent degradation. This positions TFEB as a key orchestrator of lysosomal adaptation, a cellular response that adjusts degradative capacity, metabolic flexibility, and recycling efficiency during oxidative, metabolic, or proteotoxic stress^[6].

Beyond its canonical roles in autophagy, TFEB also integrates signals from nutrient availability, mitochondrial function, and mechanistic target of rapamycin complex 1 (mTORC1) activity to regulate energy homeostasis^[7-10]. This signal-integration capacity allows TFEB to function as a dynamic stress-responsive regulator rather than a constitutive driver of lysosomal activity. These properties make TFEB particularly relevant in the context of aging, where the progressive decline in autophagic flux and lysosomal acidification contributes to the accumulation of damaged organelles and macromolecules^[11-13], and where adaptive stress responses become increasingly blunted or dysregulated^[14].

TFEB activation enables a transient, restorative response to acute cellular challenges by coordinately enhancing autophagy and lysosomal biogenesis, thereby promoting recovery of metabolic and proteostatic homeostasis. Importantly, the timing, amplitude, and resolution of this TFEB-dependent autophagic program appear critical: while short-term activation supports stress resilience through efficient autophagic flux, failure to properly terminate or re-engage TFEB signaling may impair autophagy control and influence whether cells successfully recover or instead progress toward a senescent state^[15-17]. This positions TFEB not only as a regulator of lysosomal adaptation but also as a central modulator of autophagy-dependent cell-fate decisions during stress and aging.

2. TFEB Activation Under Stress: Triggers and Signaling Pathways

Although numerous signaling inputs regulate TFEB activity, current evidence suggests a hierarchical organization in which lysosome-associated mTORC1 signaling serves as the central regulatory axis, while additional pathways fine-tune TFEB responsiveness in response to stress context. A wide range of stressors, including nutrient deprivation^[18], oxidative and mitochondrial damage^[19], lysosomal dysfunction^[20], and inflammatory cues^[21], converge on TFEB activation to enhance lysosomal and autophagic capacity. Although these stimuli differ in origin, they share a common outcome: relieving inhibitory phosphorylation on TFEB and promoting its nuclear translocation to restore cellular homeostasis (Figure 1).

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Figure 1. Regulation of TFEB activity and functional output of the CLEAR network. TFEB localization and activity are dynamically controlled by nutrient- and stress-responsive signaling pathways. Under nutrient-rich conditions, mTORC1, ERK2, Akt, and CDK4/6 promote cytosolic retention and repression of TFEB, while STUB1/CHIP links its phosphorylated state to proteasomal degradation. In contrast, stress-activated pathways including calcineurin, PP2A, AMPK, and ROS signaling promote TFEB dephosphorylation and nuclear translocation. Nuclear TFEB activates the CLEAR gene network, driving transcriptional programs involved in lysosomal function, autophagy, and cellular metabolism. TFEB: transcription factor EB; CLEAR: coordinated lysosomal expression and regulation; mTORC1: mechanistic target of rapamycin complex 1; ERK2: extracellular signal-regulated kinase 2; CDK4/6: cyclin-dependent kinase 4/6; STUB1: STIP1 homology and U-Box containing protein 1; CHIP: Cterminus of HSC70-Interacting Protein; PP2A: protein phosphatase 2A; AMPK: AMP-activated protein kinase; ROS: reactive oxygen species.

Under nutrient-rich conditions, TFEB is actively repressed to prevent unnecessary lysosomal expansion. mTORC1 phosphorylates TFEB, promoting 14-3-3 binding and cytosolic retention^[8,22,23]. This core inhibitory mechanism is reinforced by additional context-dependent regulators, including extracellular signal-regulated kinase 2 (ERK2), Akt, and cyclin-dependent kinase 4/6 (CDK4/6), which further limit TFEB nuclear localization under proliferative or growth-promoting conditions^[18,24,25]. STIP1 homology and U-Box containing protein 1 (STUB1)/Cterminus of HSC70-Interacting Protein (CHIP) further targets phosphorylated TFEB for proteasomal degradation, ensuring signal termination once stress resolves^[26].

In response to stress, multiple signaling pathways actively relieve TFEB repression and promote its nuclear accumulation. Lysosomal Ca²⁺–calcineurin signaling represents a major activation axis during starvation and metabolic stress^[27], while protein phosphatase 2A (PP2A), AMP-activated protein kinase (AMPK), and protein kinase C (PKC)/glycogen synthase kinase 3β (GSK3β) pathways provide context-specific regulation depending on oxidative, energetic, or mitochondrial stress conditions^[28-30].

Beyond phosphorylation, TFEB activity is modulated by acetylation and redox-dependent mechanisms. Sirtuin 1 (SIRT1)-mediated deacetylation enhances TFEB transcriptional activity^[31-33]. Redox-dependent regulation provides an additional layer of control over TFEB availability. Oxidative stress induces oxidation of the conserved C212 residue, promoting disulfide bond formation and TFEB oligomerization^[34], increasing TFEB availability under sustained stress.

Collectively, these regulatory layers position TFEB as a highly tunable stress-responsive hub that integrates nutrient sensing, Ca²⁺ signaling, redox status, and cell-cycle cues. Importantly, this multilayered control enables rapid but reversible TFEB activation, allowing cells to mount an adaptive lysosomal response while avoiding chronic or inappropriate engagement of autophagy–lysosome programs. This property is likely to be critical in aging tissues and during the transition from stress recovery to senescence. In this framework, a core set of conserved mechanisms, centered on mTORC1-dependent phosphorylation and lysosomal signaling, forms the primary regulatory axis of TFEB, whereas additional context-specific and emerging inputs fine-tune its activity across conditions.

3. TFEB-Driven Transcriptional Programs in Stress Recovery

TFEB coordinates a stress-responsive lysosomal biogenesis program that expands and restores the degradative compartment in response to nutrient, metabolic, or lysosomal stress. Upon activation, TFEB translocates to the nucleus and binds to CLEAR elements, a conserved E-box–like motif present in the promoters of lysosomal and autophagy-related genes. Genome-wide analyses have revealed that the CLEAR network encompasses hundreds of direct TFEB targets, including lysosomal hydrolases, vacuolar-type H+-adenosine triphosphatase (V-ATPase) subunits required for acidification, membrane proteins, trafficking regulators, and core autophagy components^[5,18].

Importantly, TFEB-driven transcription extends beyond classical lysosomal genes. As illustrated in Figure 1, CLEAR targets include genes involved in vesicle-mediated transport, transmembrane transport, membrane organization, carbohydrate and sulfur compound metabolism, protein catabolic processes, immune and inflammatory responses, and diverse stress-adaptive programs. This broader transcriptional landscape highlights that TFEB does not merely increase lysosome number but coordinates an integrated cellular clearance and metabolic adaptation program that couples degradative capacity with trafficking, signaling, and metabolic rewiring.

3.1 Lysosomal stress signaling and contextual regulation of TFEB

TFEB activity is tightly controlled by lysosome-associated mTORC1 signaling. Under nutrient-replete conditions, active mTORC1 phosphorylates TFEB, promoting 14-3-3 binding and cytosolic retention. In contrast, lysosomal or metabolic stress impairs mTORC1 activity at the lysosomal surface, leading to TFEB dephosphorylation, nuclear translocation, and activation of CLEAR-network genes that expand lysosomal and autophagic capacity. Importantly, increased TFEB-driven transcription of autophagy–lysosome genes does not necessarily translate into enhanced degradative flux, as functional autophagy depends on the integrity and coordination of the entire pathway, including lysosomal capacity and cargo clearance.

Alterations in mTORC1 signaling directly impact TFEB activity and lysosomal renewal. For example, ethanol exposure in hepatocytes induces mTORC1 hyperactivation, which reduces nuclear TFEB and impair lysosomal renewal, thereby contributing to autophagy defects and tissue injury^[35].

Conversely, mild lysosomal stressors, such as trehalose, can relieve mTORC1 inhibition, thereby activating TFEB and stimulating the global autophagy–lysosomal biogenesis response^[35].

Beyond stress responses, genetic perturbations can also rewire this lysosome-centered signaling axis. In tuberous sclerosis complex (TSC1/TSC2)-deficient cells, disrupted Ras-related GTP-binding protein C (RAGC)–mTORC1 regulation results in constitutive TFEB nuclear localization and increased lysosomal gene expression^[36].

Together, these observations indicate that TFEB activity reflects the specific configuration of lysosome-associated mTORC1 signaling. Depending on whether mTORC1 is inhibited, hyperactivated, or uncoupled from TFEB, TFEB can be transiently activated, suppressed, or constitutively engaged.

3.2 Mitochondrial stress, mitophagy, and organelle turnover

Beyond lysosomes, TFEB is rapidly engaged by mitochondrial and metabolic stress to reinforce mitophagy and organelle quality control. TFEB activation boosts the transcription of autophagy–lysosome components and coordinates their activity with mitochondrial turnover. During PTEN-induced kinase 1 (PINK1)/Parkin-mediated mitophagy, TFEB translocates to the nucleus in a Parkin- and Atg5-dependent manner to facilitate efficient clearance of damaged mitochondria^[19,37].

TFEB activation downstream of lysosomal Ca²⁺–calcineurin signalling is required for efficient clearance of damaged mitochondria in multiple contexts, including starvation, endoplasmic reticulum (ER) stress, metabolic stress, and β-cell dysfunction, where it drives transcription of mitophagy receptors like nuclear dot protein 52 kDa (NDP52) and optineurin (OPTN)^[27,38]. Importantly, TFEB also couples mitochondrial degradation with compensatory biogenesis by inducing peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) expression, thereby preserving mitochondrial mass and function^[39,40].

Across tissues, mitochondrial and oxidative stress activate AMPK, a key cellular energy sensor. AMPK regulates metabolic adaptation and organelle quality control. Upon activation, AMPK promotes TFEB nuclear translocation, in part through inhibition of mTORC1. Nuclear TFEB increases the expression of autophagy and mitophagy genes and facilitates Parkin-dependent clearance of damaged mitochondria, thereby restoring mitochondrial function^[41,42].

In more defined pathological settings, direct TFEB activation has been shown to rescue mitophagy flux in ethanol-induced cardiac damage^[43] and to limit cytokine release in tumor-associated macrophages^[44]. Collectively, TFEB acts as a conserved transcriptional regulator that links mitochondrial quality control to cellular stress recovery.

3.3 Metabolic reprogramming during stress adaptation

TFEB-driven transcriptional programs extend beyond organelle turnover to coordinate metabolic adaptation during stress. TFEB couples nutrient availability to glycolytic and lipid catabolic pathways. Starvation-induced TFEB activation promotes lipophagy and hepatic lipid breakdown through transcriptional upregulation of PGC-1α and peroxisome proliferator-activated receptor alpha (PPARα)^[9], while also enhancing whole-body energy expenditure together with TFE3^[45].

Beyond lipid metabolism, TFEB modulates glucose regulation: it regulates circadian and glucose-responsive gene networks in the liver^[46], improves endothelial glucose uptake through insulin receptor substrate 1/2 (IRS1/IRS2) induction^[47], and suppresses insulin transcription in β-cells during nutrient deprivation via direct enhancer binding^[48]. In cancer, TFEB reshapes melanoma metabolism by controlling glycolysis, glutamine uptake, cholesterol synthesis, and tricarboxylic acid (TCA) cycle flux^[49]. Together, these studies position TFEB as a key metabolic regulator that modulates glucose and lipid use to restore energy balance during stress.

Beyond its role in coordinating metabolic pathways, TFEB activity is also regulated by cellular metabolic state at the level of protein synthesis. Polyamine metabolism, particularly the age-associated decline in spermidine, controls TFEB expression through eukaryotic initiation factor 5A (eIF5A) hypusination, which is required for efficient TFEB translation and maintenance of autophagy. Restoration of this pathway enhances autophagy and improves cellular function in aged immune cells, positioning TFEB within the emerging framework of polyamine-dependent regulation of aging^[50].

3.4 Redox homeostasis and antioxidant responses

Reactive oxygen species (ROS) can directly activate TFEB through redox-sensitive mechanisms^[34,51]. In turn, TFEB induces transcriptional programs that enhance antioxidant capacity and restore organelle-specific redox homeostasis, thereby limiting oxidative damage. For example, ROS generated in peroxisomes during calcium deficiency activate TFEB, triggering pexophagy and restoring redox homeostasis^[52]. TFEB further buffers oxidative stress through metabolic rewiring: in the liver, TFEB enhances sulfur-amino-acid metabolism, cysteine availability, and glutathione synthesis, thereby strengthening antioxidant capacity^[53]. Efficient induction of these antioxidant genes also requires FAcilitates Chromatin Transcription (FACT)-mediated chromatin remodeling, as the FACT complex cooperates with TFEB/TFE3 to drive redox-responsive transcription^[54].

Failure to properly resolve these TFEB-dependent adaptive responses may contribute to the transition from reversible stress responses to stable senescence.

4. TFEB in the Transition from Stress to Senescence

A central unresolved question is how TFEB-mediated stress responses transition from adaptive programs that promote recovery to dysfunctional states associated with senescence and aging. During acute stress, transient TFEB activation supports cellular homeostasis by restoring lysosomal, metabolic, and redox balance. However, when stress is persistent or repeatedly encountered, this adaptive response becomes progressively impaired. Loss of proper TFEB inducibility, timing, or resolution limits cells’ ability to restore homeostasis, thereby promoting the accumulation of damage and favoring the transition toward senescence. In this context, aging can be conceptualized as a progressive failure of TFEB-dependent stress adaptation, linking impaired recovery from stress to the emergence of age-associated phenotypes.

The nature of the initiating stress further shapes this transition, as distinct stressors differentially engage TFEB regulatory pathways and impose specific demands on cellular clearance and metabolic adaptation. As a result, the magnitude, duration, and resolution of TFEB activation vary, thereby influencing how rapidly cells progress toward senescence.

TFEB behaves differently across senescence models, acting as an early cytoprotective factor in oxidative stress-induced premature senescence (SIPS) but a sustained survival factor in oncogene-induced senescence (OIS). In SIPS induced by oxidative stress, TFEB shows a rapid, transient nuclear activation that boosts lysosomal biogenesis and autophagic clearance to buffer ROS-induced damage in response to the stress^[15,55,56]. When the senescence program is established, however, TFEB activity declines: nuclear levels drop despite lysosomal expansion, consistent with mTORC1 reactivation and cytosolic retention overriding upstream stress signals^[57,58]. This decline parallels the transition from transient autophagy to lysosomal dysfunction, with swollen, less acidic lysosomes and impaired proteolysis leading to accumulation of aggregates and defective mitochondria^[51,59,60].

In contrast, cells in OIS maintain constitutive nuclear TFEB/TFE3 and persistent lysosomal expansion^[61,62], in line with the chronic autophagy engagement characteristic of OIS^[63,64]. Thus, while TFEB activation in SIPS is transient and resolves as cells commit to senescence, OIS cells maintain prolonged TFEB activity as part of a sustained survival program.

Functional perturbation studies support this temporal framework. In oxidative SIPS, TFEB promotes survival during the acute stress phase but does not prevent senescence commitment^[15]. TFEB knockdown shifts tert-butyl hydroperoxide (tBHP)-treated cells toward apoptosis, reducing the number of cells that reach senescence, whereas TFEB overexpression enhances early stress tolerance without blocking the eventual acquisition of senescence markers. Together, these findings indicate that TFEB defines a short-lived resilience window following stress, whose closure marks commitment to stable senescence^[15].

Beyond stress-induced and oncogene-driven senescence, MiT/TFE family members also appear to be engaged during replicative senescence. Curnock et al. reported increased nuclear localization of TFE3 across all senescence models examined, including replicative senescence^[61], accompanied by reduced lysosomal degradative activity that was partially compensated by increased lysosomal content. Whereas TFEB and TFE3 share overlapping target genes and are regulated by similar upstream signaling pathways, further studies will be required to precisely delineate their overlapping versus distinct functions in aging cells and during cellular senescence.

Together, these observations suggest that replicative senescence, like other senescence modalities, is associated with sustained MiT/TFE nuclear activity, while the specific contribution and temporal dynamics of TFEB in this context remain to be fully resolved.

5. TFEB Dysfunction in Aging and Age-Related Diseases

Aging is associated with a progressive impairment of TFEB-dependent lysosomal and autophagy programs, resulting in reduced proteostasis and stress resilience across tissues. Importantly, this dysfunction does not primarily reflect loss of TFEB expression, but rather defects in its regulation, including altered upstream signaling, impaired nuclear translocation, and reduced transcriptional or translational competence^[65]. As a consequence, the dynamic inducibility and resolution of TFEB activity become compromised (Figure 2), limiting adaptive lysosomal responses and favoring the accumulation of damaged organelles and protein aggregates characteristic of aged cells^[66,67].

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Figure 2. Loss of dynamic TFEB responsiveness during aging. Young cells display inducible and reversible TFEB nuclear activity that supports proteostasis, whereas aged cells exhibit blunted TFEB dynamics associated with impaired lysosomal adaptation and aggregate accumulation. TFEB: transcription factor EB.

Importantly, studies in invertebrate model organisms support an evolutionarily conserved role for MiT–TFE factors in aging and longevity. In Caenorhabditis elegans, the TFEB ortholog HLH-30 regulates autophagy and lysosomal gene expression and is required for lifespan extension across multiple longevity paradigms, with its nuclear localization and overexpression promoting organismal longevity^[68]. Similarly, in Drosophila melanogaster, the homolog Mitf controls lysosomal-autophagic pathways through transcriptional regulation of V-ATPase and CLEAR network genes, and its activity declines with age, linking MiT–TFE dysfunction to impaired proteostasis in vivo^[69,70]. Together, these findings indicate that TFEB/MiT–TFE-dependent control of lysosomal function is a deeply conserved mechanism that not only becomes dysregulated during aging in mammals but also acts as a fundamental determinant of lifespan across species.

5.1 Mechanisms and tissue-specific consequences of TFEB dysfunction during aging

Aging is associated with a progressive disruption of TFEB regulation across multiple tissues, driven by both signaling-mediated inhibition and altered nucleocytoplasmic trafficking. In the nervous system, age-related increases in calcineurin inhibitors, together with enhanced chromosomal region maintenance 1/exportin 1 (CRM1/XPO1)-dependent nuclear export, restrict TFEB nuclear residency and attenuate lysosomal gene expression, contributing to proteostasis collapse in neurodegenerative contexts^[71-73]. These studies suggest that these mechanisms are conserved across humans, mice, and C. elegans, supporting the idea that excessive nuclear export represents a general hallmark of aging-associated TFEB dysregulation.

Beyond the nervous system, impaired TFEB activation has been implicated in a broad range of age-related pathologies, including chronic lung disease, cardiovascular dysfunction, and renal aging, where defective stress-induced TFEB responses exacerbate tissue injury and inflammation^[74,75]. In zebrafish models of cardiac aging, restoration of TFEB activity downstream of mTOR improves proteostasis and delays senescence-associated functional decline, highlighting a direct role for TFEB in shaping cardiac aging trajectories^[76]. Conversely, age-dependent loss of TFEB nuclear localization in renal proximal tubules disrupts lysosomal and mitochondrial homeostasis, contributing to systemic metabolic alterations and amyloid deposition, underscoring a causal link between TFEB decline and renal aging^[77].

Notably, TFEB activation is not universally beneficial in aging tissues. In chronic kidney disease models, sustained or excessive activation of autophagy–lysosome pathways promote inflammation and fibrosis, illustrating that inappropriate or prolonged TFEB activity can become maladaptive^[78]. Together, these observations indicate that aging is characterized not simply by reduced TFEB activity, but by a loss of dynamic and context-appropriate TFEB regulation, mirroring the altered TFEB dynamics observed during the transition from stress adaptation to stable senescence.

Mechanistically, these alterations reflect a progressive failure of interconnected TFEB-dependent homeostatic pathways. Reduced TFEB activity impairs autophagy–lysosome function, leading to the accumulation of damaged proteins and organelles and to proteostasis loss. In parallel, defective clearance disrupts mitochondrial quality control, promoting dysfunctional mitochondria, increased reactive oxygen species, and metabolic inflexibility. Blunted TFEB-dependent antioxidant and metabolic programs further exacerbate oxidative stress and energy imbalance. Together, these defects reduce cellular resilience and stress adaptation, ultimately driving tissue dysfunction and age-associated decline. Thus, TFEB acts as a central integrator of proteostatic, metabolic, and redox pathways, and its loss of dynamic regulation underlies key hallmarks of aging.

5.2 Therapeutic modulation of TFEB activity in aging

Given the multifactorial dysregulation of TFEB during aging, diverse genetic and pharmacological strategies have been explored to restore TFEB activity or modulate its downstream effects (Table 1). These interventions target distinct regulatory layers, including upstream mTORC1 signaling, metabolic inputs, nucleocytoplasmic trafficking, and tissue-specific TFEB expression.

Several pharmacological and metabolic interventions converge on TFEB activation, most prominently through mTORC1 inhibition, which promotes TFEB dephosphorylation and nuclear translocation and has shown protective effects in age-related and proteostasis-driven pathologies^[79]. However, because mTORC1 controls multiple anabolic and stress-responsive pathways, mTORC1 inhibition may produce off-target or TFEB-independent effects that contribute to the observed phenotypes.

Metabolic modulators, such as statins, can indirectly enhance TFEB activity and have been associated with improved outcomes in age-related hearing loss^[80]. In parallel, limiting TFEB nuclear export via CRM1/XPO1 inhibition increases nuclear retention and has been linked to lifespan extension in neuronal aging models^[73].

More recent approaches directly target TFEB itself, including small-molecule TFEB activators and tissue-specific TFEB overexpression strategies, which restore proteostasis and delay functional decline in aging tissues^[76,81]. A recent study in C. elegans identified a small molecule that extends lifespan by inducing TFEB-dependent mitophagy, involving transcriptional upregulation of TFEB through nuclear hormone receptor signaling, thereby expanding current models beyond post-translational control^[82]. Importantly, accumulating evidence indicates that restoring physiological TFEB responsiveness, rather than sustained activation, is sufficient to enhance stress resilience during aging, as chronic hyperactivation of autophagy–lysosome pathways can become maladaptive and promote inflammation and fibrosis in disease contexts^[78]. These observations underscore the need for temporal and tissue-specific precision when considering TFEB-based interventions in aging and age-related diseases.

6. Outlook: TFEB Modulation as a Therapeutic Opportunity in Geromedicine

The studies reviewed here converge on the view that TFEB plays a central role in coordinating lysosomal, metabolic, and stress-adaptive programs, but that its contribution to aging and age-related disease is fundamentally shaped by context and timing. Evidence from SIPS indicates that TFEB activation supports early stress adaptation by enhancing lysosomal and autophagic programs, which may not necessarily translate into effective degradative flux, yet this response is transient and does not prevent senescence commitment. Instead, loss of TFEB nuclear activity during the stabilization phase of SIPS coincides with lysosomal dysfunction and irreversible senescent features, highlighting TFEB as a regulator of stress adaptation rather than a universal determinant of senescence avoidance.

This temporal behavior contrasts with observations in other senescence models, such as oncogene-induced senescence, where sustained MiT/TFE activity accompanies chronic autophagy engagement, and with aging tissues, where TFEB dysfunction often reflects impaired inducibility, altered nucleocytoplasmic trafficking, or post-transcriptional regulation rather than reduced expression. Together, these findings underscore that TFEB activity can be either adaptive or maladaptive depending on tissue context, stress history, and metabolic state. Beneficial effects are typically associated with transient TFEB activation that supports stress resolution and recovery, whereas persistent, dysregulated, or insufficient activation compromises proteostasis and promotes maladaptive outcomes, including inflammation or fibrosis. This has important implications for intervention, as emerging strategies to manipulate TFEB function must carefully balance activation magnitude and duration to avoid paradoxically exacerbating these outcomes.

In this context, TFEB can be positioned within the broader framework of the hallmarks of aging, linking stress adaptation to core processes such as proteostasis, mitochondrial quality control, and nutrient sensing by regulating lysosomal degradation, coordinating autophagy–lysosome pathways, and integrating metabolic signals. This coupling helps explain why TFEB activation can promote cellular recovery in some settings yet contribute to maladaptive responses, such as persistent autophagy or inflammation, in others.

Taken together, the available evidence supports a model in which TFEB functions as a context-dependent regulator of cellular resilience, with precise temporal modulation, rather than constitutive activation, offering therapeutic benefit. From a geromedicine perspective, strategies aimed at restoring physiological TFEB responsiveness during defined stress windows could enhance cellular fitness and delay functional decline, while avoiding the risks associated with chronic activation of degradative pathways. Defining the conditions under which TFEB promotes recovery versus maladaptation, and identifying tissue-specific windows of intervention, therefore, remains a critical challenge for translating TFEB modulation into effective anti-aging or senolytic strategies.

Acknowledgments

The authors declare that artificial intelligence (AI) tools were used solely to assist with language editing and text refinement.

Authors contribution

Guerrero-Navarro L: Conceptualization, writing-original draft.

Jansen-Dürr P: Writing-review & editing.

Cavinato M: Conceptualization, writing-original draft, writing-review & editing.

Conflicts of interest

The authors declare no conflict of interest.

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© The Author(s) 2026.