Mechanotransduction for therapeutic approaches: Cellular aging and rejuvenation

Hye-Min Han; Su-Yeon Kim; Dong-Hwee Kim

doi:10.1063/5.0263236

. 2025 Jun 6;9(2):021502. doi: 10.1063/5.0263236

Mechanotransduction for therapeutic approaches: Cellular aging and rejuvenation

Hye-Min Han ¹, Su-Yeon Kim ², Dong-Hwee Kim ^1,3,4,^a)

PMCID: PMC12145204 PMID: 40488107

Abstract

Mechanotransduction regulates cytoskeletal remodeling, nuclear mechanics, and metabolic adaptation, which are central to cellular aging and rejuvenation. These responses restore mechanical balance in aged cells, reprogram longevity-related gene expression, and alleviate age-related disorders, including neurodegeneration, musculoskeletal decline, and cardiovascular dysfunction. These insights indicate that mechanotransduction is pivotal in cellular and systemic processes underlying aging. The key signaling pathways, including the Hippo/Yes-associated protein (YAP), mechanistic target of rapamycin (mTOR), and transforming growth factor-beta (TGF-β)/Smad, have been explored in mediating age-related physiological decline, showing potential as therapeutic targets. Aging-dependent stiffening of the extracellular matrix (ECM) is associated with accelerated senescence. Interventions targeting ECM remodeling, such as mechanochemical therapies and nanoparticle delivery systems, provide promising strategies for counteracting cellular deterioration. Research progress has elucidated the critical role of mechanotransduction in organ-specific aging, enabling targeted interventions that align mechanical and biochemical therapeutic strategies. This review highlights the integration of mechanical modulation into therapeutic approaches, emphasizing its potential to restore cellular functionality, improve health, and extend lifespan. Advances in mechanomedicine have opened innovative frontiers in combating aging and age-associated diseases by addressing the interplay between mechanical forces and cellular processes. Cellular rejuvenation—the restoration of aged cells to a functionally younger state through the regulation of mechanotransduction pathways—involves the reversal of senescence-associated phenotypes, including nuclear deformation, mitochondrial alterations, and ECM stiffness. Furthermore, mechanotransduction plays a critical role in cellular rejuvenation by modulating YAP/TAZ activity, promoting autophagy, and maintaining cytoskeletal integrity.

I. INTRODUCTION

Aging is a complex biological process in living organisms and is regulated not only by genetic and biochemical factors but also by mechanical cues that influence cellular function and longevity.^1,2 Mechanical signals, including ECM stiffness, cytoskeletal tension, and nuclear deformation, modulate transcriptional responses, epigenetic remodeling, and mitochondrial homeostasis, thereby contributing to cellular senescence and rejuvenation. Mechanotransduction is a fundamental process through which mechanical stimuli, such as the ECM stiffness and cytoskeletal forces, are converted into biochemical signals that regulate cellular aging.^3,4 Unlike purely biochemical aging mechanisms, mechanotransduction influences cellular senescence through force-dependent changes in nuclear architecture, mitochondrial function, and chromatin organization.⁵ Understanding the mechanical regulation of aging is essential for developing mechanomedicine-based interventions.⁶ Mechanotransduction plays a key role in this process by transmitting mechanical forces from the ECM to the nucleus through cytoskeletal linkages, activating signaling pathways such as Hippo/YAP, TGF β/Smad, and mTOR, which govern cellular responses to mechanical stimuli.⁷

Cellular rejuvenation relies not only on pharmacological interventions but also on mechanotransduction-based strategies aimed at restoring cellular homeostasis by modulating mechanical forces at the subcellular level.⁸ Mechanically induced nuclear deformation, cytoskeletal realignment, and ECM remodeling play critical roles in reversing age-associated cellular dysfunctions as well as disease progression. Furthermore, force-mediated nuclear remodeling directly affects chromatin compaction and gene expression, which promote regenerative transcriptional programs and delay the onset of senescence.⁹

For instance, controlled mechanical stimulation has been shown to enhance mitochondrial biogenesis, reduce oxidative stress, and reprogram chromatin organization, thereby improving the regenerative potential of aged cells.¹⁰ Biophysical interventions such as tuning the substrate stiffness and cyclic stretching can restore stem cell function and delay cellular senescence.¹⁰

Aging is broadly characterized by a gradual decline in functional capacity and homeostasis, accompanied by increased vulnerability to diseases. A representative example of normal aging that progresses gradually in the absence of disease is the change in cell motility.¹¹ As biological age increases, cell motility decreases due to fractional redistribution in the motile state.¹² Examining similarities in the movement of skin fibroblasts has revealed that cells from younger individuals tended to move in a specific direction, whereas those from aging individuals exhibited limited directional movement and heterogeneity in their motility.¹²

Typical age-related diseases include high blood pressure and atherosclerosis, which can lead to various cardiovascular diseases and ultimately result in death.¹³ Aging can be explained by the distinction between pathological and normal aging. For instance, age-associated memory impairments, such as mild cognitive impairment, are classified as normal aging conditions, whereas dementia is classified as pathological aging.¹⁴ Mild cognitive impairment occasionally involves forgetting words, names of objects, or conversations from at least 1 year ago, whereas Alzheimer's disease (AD) involves forgetting or failing to recognize family members and an inability to remember recent conversations.¹⁴

ECM stiffening, a hallmark of tissue aging, disrupts cellular mechanotransduction and alters the mechanical properties of the microenvironment, thereby exacerbating age-related pathologies by changing cellular responses to mechanical stimuli.¹⁵ For instance, age-related stiffening of vascular tissues impairs endothelial cell mechanotransduction, leading to reduced nitric oxide bioavailability and increased vascular resistance.¹⁶ With aging, musculoskeletal tissues in muscles, tendons, and joints undergo structural changes; e.g., collagen becomes more tightly cross-linked, and the amount of proteoglycans decreases. These changes increase the tissue stiffness but reduce elasticity, resulting in cellular aging.¹⁷ These systemic alterations provide a mechanobiological basis for cellular aging, influencing intracellular signaling cascades and stress responses.³

Cellular aging is intricately linked to mechanical changes in the microenvironment, such as ECM stiffening. These changes exacerbate age-related pathologies by altering the cellular responses to mechanical stimuli.¹⁸ This response pathway transmits signals from outside of the cell to the cytoplasm and nucleus¹⁹ via LINC complexes and nuclear lamin proteins, which transmit cytoplasmic signals to the interior of the nucleus.^5,20 The process of recognizing mechanical stimuli in an external environment is termed mechanosensation,²¹ where integrins, actin cytoskeletal networks, and piezo channels play critical roles.^22–24 Moreover, mechanotransduction is a fundamental regulator of aging, regulating multiple cellular functions such as ECM stiffness, cytoskeletal tension, and nuclear deformation.²⁵ These mechanical cues activate intracellular signaling pathways such as Hippo/YAP, TGF β/Smad, and mTOR, coordinating cell fate decisions, proliferation, and differentiation,^3,26 ultimately shaping the aging process through subcellular mechanotransduction.

Nuclear mechanotransduction is critical in cellular aging by altering chromatin organization and DNA repair capacity.²⁷ Age-related changes in nuclear lamina composition impair DNA damage responses (DDRs), leading to genomic instability and increased cellular stress.⁵ Mechanical modulation strategies, such as those based on controlling substrate stiffness and cyclic stretching, have demonstrated efficacy in restoring mechanotransduction balance, thereby mitigating aging-associated dysfunctions.¹ Mechanical signals affect mitochondrial function and reactive oxygen species (ROS) production.^28,29 The signal generated by the interaction between the ECM and integrin induces ROS production through the Ras homolog (Rho) family of guanosine triphosphatases (GTPase).^30–33 In addition, the elasticity and stiffness of the ECM change the shape and differentiation of cells, accelerating or delaying aging.^1,15,17,34

This review explores the mechanobiological perspectives on cellular aging and recent advances in mechanomedicine contributing to cellular rejuvenation and further discusses the mechano-modulation of age-associated therapeutic challenges.

II. THE BIOLOGY OF AGING: CELLULAR AND SYSTEMIC PERSPECTIVES

A. Aging at the systemic level

Aging is a systemic process driven by progressive alterations in tissue architecture, mechanical homeostasis, and cellular metabolism. At the organ level, aging is characterized by ECM remodeling, increased fibrosis, and impaired intercellular communication, all of which contribute to functional decline.³⁵ Age-related stiffening of vascular tissues impairs endothelial cell mechanotransduction, which leads to reduced nitric oxide bioavailability and increased vascular resistance.³⁶ Degenerative changes in musculoskeletal tissues, such as increased collagen cross-linking and loss of proteoglycan content, exacerbation of stiffness, and impaired tissue elasticity.³⁷ These systemic alterations provide a mechanobiological basis for cellular aging, influencing intracellular signaling cascades and stress responses.³⁸

Aging is a progressive process that affects tissue structure, function, and homeostasis through multiple interconnected mechanisms.³⁹ A primary driver of aging is oxidative stress, which results from an imbalance between ROS production and antioxidant defenses.⁴⁰ Excessive ROS generation damages cellular components, including DNA, proteins, and lipids, leading to impaired cellular function and senescence.²⁸ Accumulated oxidative damage contributes to mitochondrial alterations, reduced ATP production, and altered metabolic homeostasis, all of which are critical factors in aging-related tissue degeneration.⁴¹

Another key contributor to aging is telomere shortening, which occurs due to the progressive loss of chromosomal end regions during cell division. Critically short telomeres trigger DDRs, leading to cell cycle arrest, senescence, or apoptosis.⁴² This process depletes the regenerative capacity of stem cell populations, reducing tissue maintenance and repair potential.⁴² Simultaneously, the ECM remodeling and increased fibrosis further disrupt tissue integrity, exacerbating organ dysfunction.⁴³

As a result of these interconnected mechanisms, aging impairs the function and homeostasis of tissues and organs, depletes the number of functional cells, and alters their structural properties.⁴⁴ These systemic changes contribute to increased susceptibility to age-related diseases, including neurodegeneration, cardiovascular disorders, and metabolic dysfunction.²

This can result in severe metabolic dysfunction and tissue atrophy. A comparative analysis of metabolic products in the brain, heart, kidneys, liver, lungs, and spleen of younger and aging rats revealed that the concentrations of branched-chain amino acids and gamma aminobutyric acid were increased in aging rats, while their uridine levels were decreased.⁴⁵ Branched-chain amino acids are known to increase the risk of cardiovascular diseases, and gamma aminobutyric acid can impair cardiac function.^46,47 Reduced uridine levels promote cellular senescence in various tissues, including the spleen and mammary glands.⁴⁸ In brief, aged cells are in a state of hypermetabolism and the resulting increases or decreases in metabolic products can impair the functions of various tissues and organs. Primary mitochondrial oxidative phosphorylation also causes hypermetabolism and accelerates aging.⁴⁹

A notable example of aging is inflammaging, a chronic low-grade inflammation that occurs as people age.⁵⁰ Although inflammation generally provides strong resistance to infectious diseases and aids survival during childhood, it often has detrimental effects in aging populations.⁵¹ Inflammaging is associated with the accumulation of tissue damage, organ damage, and functional dysregulation.⁵² Inflammaging is primarily induced by inflammatory cytokines secreted by aged cells. This process activates the nuclear factor-κB (NF-κB) transcription factor and increases the production of ILs and interferons, thereby impairing the immune system.^50,53 Excessive ROS accumulation in the mitochondria induces the activation of nucleotide-binding domain, leucine-rich repeat, and pyrin domain-containing protein 3 (NLRP3) activations, thereby promoting the secretion of caspase 1 (CASP1)-dependent interleukin (IL)-1β.^54–56 NLRP3 is the primary sensor of intracellular danger-associated molecular patterns (DAMPs), as it activates the inflammasome upon recognizing DAMPs.⁵⁷ Inflammatory CASP1 matures and promotes the secretion of the precursors of IL-1β and IL-18.⁵⁰ This process contributes to atherosclerosis, type 2 diabetes, and AD pathogeneses.^50,58,59

Adipose tissue is the most affected by aging.⁶⁰ As adipose tissue ages, the amount of stored fat increases and then decreases sharply, with a decrease in subcutaneous fat and an increase in visceral fat.^61,62 This shift increases the risk of metabolic abnormalities and insulin resistance.^62,63 Furthermore, these changes are attributed to a decline in stem cell function and accumulation of senescent cells.^64,65

B. Causes of cellular senescence

Critical factors that induce cellular senescence include ROS, DNA damage, lack of NAD⁺, and ECM metabolism.⁶⁶ ROS accumulation-mediated cellular senescence has been induced by knocking down nuclear factor erythroid 2 (NRF2), a major transcription factor that regulates the antioxidant response and protects cells from oxidative stress.⁶⁷ ROS trigger a senescence-associated secretory phenotype (SASP), driving the secretion of inflammatory cytokines and growth factors.²⁸ This process induces chronic inflammation in surrounding cells, creating a microenvironment conducive to cancer development.^68,69 Mitochondrial dysfunction is tightly regulated by mechanical forces.⁷⁰ Increased ECM stiffness and disruption of cytoskeletal organization can impair mitochondrial dynamics, leading to altered bioenergetics, ROS overproduction, and premature cellular senescence.⁷¹ Restoring mechanotransduction homeostasis enhances mitochondrial function and delays age-associated metabolic decline.⁷² In aged tissues, mitochondrial impairment disrupts ATP production, increases cellular rigidity, and enhances ECM degradation.⁷⁰ This metabolic dysfunction propagates aging-associated tissue degeneration, particularly in energy-demanding organs such as the brain and cardiovascular system.⁷³ In aging cells, mitochondrial dysfunction increases ROS leakage from the electron transport chain, which overwhelms antioxidant defenses.⁵³ This imbalance causes oxidative damage to mitochondrial DNA, lipids, and proteins, further deteriorating mitochondrial function.⁷⁴

Mechanical cues directly influence cellular aging by modulating nuclear stiffness, DDR pathways, and mitochondrial homeostasis.⁷⁵ ECM stiffening alters nuclear lamina composition, leading to impaired DNA repair and increased telomere attrition. This mechanotransduction-driven telomere dysfunction accelerates cellular senescence independently of classical oxidative stress pathways.⁷⁶

Telomere shortening causes DNA damage. Telomerase expression in immortalized human fibroblasts reduced progerin mRNA expression by 3- to 10-fold compared to that in wild-type cells.⁷⁷ Telomere dysfunction induces the alternative splicing of cytoskeleton-related genes, leading to cytoskeletal reorganization during cellular aging.⁷⁷ NAD⁺ is an essential coenzyme for cellular energy metabolism and DNA repair, regulating the activity of NAD⁺-dependent deacetylases such as sirtuin1.^78,79 When NAD⁺ levels decline, sirtuin1 activity decreases, leading to senescence through the p53 and p16INK4a pathways.⁸⁰ Sirtuin1 activates the transcription factor EB through the sirtuin1 mTOR pathway.⁸¹ EB increases autophagy, leading to the removal of aging-induced dysfunctional organelles and the generation of new organelles.⁸² NAD⁺ deficiency results in poly-adenosine diphosphate ribose polymerase-1 overactivation, accelerates NAD⁺ depletion, and impairs the DNA repair capacity.¹² Reduced NAD⁺ levels also impair mitochondrial function, increase ROS production, and induce cellular senescence through oxidative stress.⁸⁰

Degradation and remodeling of ECM components such as collagen, elastin, and proteoglycans are essential for maintaining cellular function and tissue structure. However, aging disrupts ECM homeostasis, leading to altered mechanotransduction signaling and cellular dysfunction.³ Age-related ECM stiffening activates integrin-mediated focal adhesion kinase signaling, which in turn promotes actomyosin contractility and nuclear deformation, accelerating cellular senescence.⁸³ Increased ECM cross-linking also enhances TGF-β signaling, which drives fibrosis and inflammation, further contributing to age-associated tissue degeneration.⁸⁴ ECM degradation is primarily regulated by matrix metalloproteinases (MMPs); their overactivation compromises the structural integrity of the ECM, leading to cellular senescence.⁸⁵ Alterations in the ECM activate intracellular signaling pathways through receptors such as integrins on the cell surface, while also induces senescence.⁸⁵ The integrin α6β4 Src protein kinase B (AKT) signaling pathway plays a role in inhibiting apoptosis and induces cellular senescence in irradiated tumor cells.⁸⁶ This pathway activates AKT, which increases the expression of anti-apoptotic proteins and suppresses pro-apoptotic protein activity.⁸⁶ Cells enter the senescence pathway as a survival mechanism despite unrepaired DNA damage. This process can alter the tumor microenvironment and potentially increase therapeutic resistance.⁸⁶ Moreover, reduced expression of yes-associated protein/transcriptional coactivator with PDZ binding motif (YAP/TAZ) leads to mechanotransduction and promotes cellular aging.^87,88 The decreased activity compromises the integrity of the nuclear envelope, leading to DNA leakage into the cytoplasm.⁸⁹ Activated stimulation of the interferon gene increases inflammatory cytokine expression, driving chronic inflammation and cellular aging.⁹⁰

C. Cellular aging and senescence

Organisms undergo epigenetic alterations during normal aging. NAD-dependent deacetylase contributes to healthy aging by regulating genome stability by deacetylating mitochondrial proteins and histone H3K9.^2,91,92 Since aging is associated with chromatin remodeling, such as a reduction in the share of heterochromatin across overall chromatin,⁹³ transcriptional noise also increases, leading to abnormal production and maturation of noncoding RNAs, such as microRNAs (miRNAs), which impede smooth regulation of stem cell behavior.⁹⁴ Consequently, aging leads to stem cell depletion and alterations in intercellular signaling.^2,95–97 A decrease in the number of hematopoietic stem cells reduces immune cell production, whereas a shortage of muscle stem cells results in fewer muscle fibers.^98,99 These conditions can lead to immunosenescence and sarcopenia, respectively.⁹⁸

Senescence is a state of cell cycle arrest that can induce inflammation in surrounding tissues and potentially contribute to oncogenesis. One hallmark of cellular senescence is the increased activity of senescence-associated β-galactosidase (SA-β-gal).^100,101 Increased SA-β-gal expression is a representative biomarker for cellular senescence.¹⁰⁰ The importance of a lamin-based detection method is emphasized as an alternative biomarker for SA-β-gal. Lamin B1 is a critical biomarker for identifying senescent cells. Lamin B1 is an inner nuclear membrane protein that adheres heterochromatin to the inner nuclear membrane by recognizing and binding to the lamina-associated heterochromatin domain.¹⁰² Reduced lamin B1 levels indicate that the composition or shape of the nuclear membrane is significantly altered as the cell enters senescence because it is connected to the cytoskeleton through the nuclear membrane¹⁰³ (Table I).

TABLE I.

Age-dependent variations in cellular responses compared between young and senescent cells relative to baseline parameters.

Aging marker	Young cells	Senescent cells	References
Single-cell motility	Fast	Slow	2, 12, 93, 99
Single-cell morphology	Elongated	Round, large	12, 322
Single-cell division	Active division	Senescence	2, 323
Adipose tissue	Stable amount of stored fat	Sharply fluctuated amount of stored fat	60, 61
Skin elasticity	High elasticity	Low elasticity	324, 325
Epigenetic alterations	Less change	More change	93
β-galactosidase	Low expression	High expression	100
P-series proteins (p53, p21, and p16)	Low	High	108, 326
Senescence-associated secretory phenotype (SASP) secretome	No SASP secretion	SASP secretion	2, 110, 327
Lamin B1	High lamin B1	Low lamin B1	328
Reactive oxygen species	Low oxidative stress	High oxidative stress	324, 329
Telomere	Long telomere	Short telomere	323, 330–332
NAD+	High NAD+	Low NAD+	63, 89
Stem cell depletion	Abundant stem cell	Stem cell shortage	98, 99
Extracellular matrix (ECM)	Dense ECM	Loose ECM	85, 86
Cell metabolism	Normal metabolism	Hypermetabolism	12
Inflammation	Normal inflammation	Inflammaging	50, 98

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Increased P-series protein expression is another characteristic of senescence. DNA damage caused by 8-oxoguanine, which is induced by ROS or telomere shortening, increases p53 expression, which may lead to apoptosis or senescence.^104–107 ROS impair mitochondrial activity and increase ROS production, which exacerbates oxidative stress and accelerates senescence.⁴¹ p21 is frequently used as a marker for DNA damage-induced senescence because it plays a crucial role in maintaining the viability of DNA damage-induced senescence cells.¹⁰⁸ P21 is a representative cyclin-dependent kinase inhibitor that forms a complex with cyclin-dependent kinase and causes cell cycle arrest.¹⁰⁹ This finding can be attributed to the increased DNA damage during mitosis in the absence of p21, which leads to a strong DDR that induces cell death through caspases and c-Jun N-terminal kinase.¹⁰⁸ The SASP secretome is another hallmark of senescence. SASP factors secreted by senescent cells cause inflammation and senescence in surrounding healthy cells.¹¹⁰ SASP is heterogeneous and varies depending on the cell type, with the presence of IL-6 and IL-8 identified as a typical feature.¹¹¹

III. BIOCHEMICAL PATHWAYS FOR AGING-ASSOCIATED MECHANOTRANSDUCTION

A. The TGF-β/Smad pathway

Mechanical signals regulate cellular aging through various biochemical pathways (Fig. 1). For example, mitochondrial function and ROS production are highly sensitive to extracellular physical settings.^28,29 The signal generated by the interaction between the ECM and integrin induces ROS production through the Rho family of GTPase.^30–33 The elasticity and stiffness of the ECM change the shape and differentiation of cells, accelerating or delaying aging.^1,15,17,34

As tissues age, ECM stiffness increases due to enhanced collagen cross-linking and reduced elastin content, altering cellular mechanosensing and triggering aberrant mechanotransduction signaling.¹⁵ One of the primary pathways influenced by ECM stiffening is the Hippo/YAP signaling cascade. Under physiological conditions, soft ECM environments support YAP/TAZ cytoplasmic sequestration, maintaining cellular quiescence and homeostasis.²⁶ However, in aged tissues, increased ECM rigidity promotes YAP/TAZ nuclear translocation, driving fibroblast activation, fibrosis, and cellular dysfunction.⁷ ECM stiffening enhances integrin-mediated focal adhesion signaling, leading to sustained activation of RhoA and actomyosin contractility, which further propagates cellular aging.³ Controlled mechanical cues such as cyclic stretching and soft substrate environments can mitigate age-related decline by restoring proper mechanotransduction signaling. These interventions promote autophagy, enhance mitochondrial function, and support stem cell renewal, thereby counteracting the detrimental effects of ECM aging.¹

The TGF-β signaling pathway is highly mechanosensitive, responding to ECM stiffness and cellular contractility.¹¹² Increased ECM tension promotes TGF-β activation, leading to Smad-dependent transcriptional changes that drive fibrosis, senescence, and inflammatory responses in aging tissues.¹¹³ ECM stiffening during aging enhances integrin-mediated mechanotransduction, leading to aberrant activation of FAK, RhoA signaling, and YAP/TAZ nuclear translocation.²⁶ These mechanotransduction events promote actomyosin contractility, nuclear envelope deformation, and transcriptional reprogramming toward a senescent phenotype.⁹

TGF-β ligands bind to a Type II TGF-β receptor (TGFβR II) on the cell surface, and this receptor–ligand interaction induces the recruitment and Type I TGF-β receptor (TGFβR I) phosphorylation by TGFβR II.¹¹⁴ Activated TGFβR I propagates the signal downstream through the phosphorylation of receptor-regulated Smads, specifically Smad2 and Smad3.¹¹⁵ After phosphorylation, Smad2 and Smad3 undergo conformational changes, enabling them to dissociate from their receptors and form complexes with Smad4.¹¹⁵ The Smad2/3–Smad4 complex translocates to the nucleus and functions as a transcriptional regulator. TGF-β has an arginine–glycine–aspartic acid motif in latency-associated peptide and can bind to αVβ6 and αVβ8 integrins.^116,117 Among these, αVβ6 integrins are linked to the cytosolic actin cytoskeleton, transmitting contractile force to the latency-associated peptide of TGF-β and releasing TGF-β ligands.^112,118,119 Cellular tension and polarity also cause the release of active TGF-β.^112,120 For example, treatment with a Rho/Rho-associated protein kinase inhibitor may collapse the physical separation between TGFβR I and TGFβR II, enabling these two receptors to form an active signal transmission complex.^120,121

In terms of aging, dysregulation of TGF-β/Smad signaling leads to microglial activation, contributing to neuroinflammation and neuronal damage that can lead to AD.^122,123 Increased TGF-β/Smad signaling elevates susceptibility to fibrosis in the kidneys, liver, and lungs because increased TGF-β/Smad signaling contributes to the accumulation of ECM components and tissue fibrosis.¹²⁴ Smad2/3 activation promotes ECM accumulation through the expression of various fibrotic genes, including collagen,¹²⁵ proteoglycans,¹²⁶ connective tissue growth factors,¹²⁷ and MMPs.¹²⁸ TGF-β1 is concentrated in ECM by direct binding to fibrillin microfibers, accelerating fibrosis.^84,129

B. Wingless-related integration site (Wnt)/β-catenin pathway

The Wnt/β-catenin signaling pathway is a mechanism that plays pivotal roles in embryonic development,¹³⁰ tissue homeostasis,¹³¹ and disease pathogenesis,¹³² including cancer.¹³³ The pathway is initiated when Wnt proteins bind to frizzled receptors and co-receptors, such as low-density lipoprotein receptor-related proteins 5 and 6, on the cell surface.¹³⁴ Upon receptor activation, the cytoplasmic protein Disheveled is recruited to the receptor complex and undergoes phosphorylation.¹³⁴ Activated Disheveled inhibits the activity of the β-catenin destruction complex, which includes Axin, adenomatous polyposis coli, glycogen synthase kinase 3β, and casein kinase 1.⁸⁰ In the absence of Wnt signaling, this destruction complex continuously phosphorylates β-catenin, targeting it for ubiquitination and proteasomal degradation.¹³⁵ Destruction complex inhibition leads to β-catenin stabilization and accumulation in the cytoplasm.¹³⁵ The accumulated β-catenin then translocates into the nucleus and functions as a transcriptional coactivator.¹³⁶

Within the nucleus, β-catenin interacts with transcription factors of the T-cell factor/lymphoid enhancer factor family.¹³⁴ The Wnt/β-catenin pathway is tightly regulated by various mechanisms to prevent overactivation. Dickkopf and secreted frizzled-related proteins can bind to Wnt receptors or ligands, blocking their interactions and inhibiting the Wnt pathway.¹³⁷ The activity of the β-catenin destruction complex can be restored, thereby ensuring the degradation of β-catenin and termination of the signal.¹³⁸ Wnt/β-catenin signaling is affected by the mechanical transformation of cells. When the mechanical transformation is applied to stationary epithelial cells, the transcriptional activity of β-catenin increases, and it accumulates in the nucleus.¹³⁹ The accumulated β-catenin causes the cell cycle to reenter the phase.¹³⁹

The Wnt/β-catenin signaling pathway plays an essential role in translating mechanical forces into transcriptional programs that govern cell proliferation, differentiation, and senescence.¹³⁹ Mechanical cues such as substrate rigidity, uniaxial stretching, and fluid shear stress can stimulate the activation of Wnt ligands, leading to enhanced β-catenin stabilization and nuclear accumulation.¹⁴⁰ ECM compression and cyclic tensile strain can facilitate the recruitment and phosphorylation of Disheveled, which inhibits the β-catenin destruction complex.¹⁴¹ This allows β-catenin to translocate into the nucleus where it interacts with TCF/LEF transcription factors, thereby regulating the expression of the genes involved in tissue remodeling and stem cell maintenance.¹⁴²

In the context of aging, ECM stiffening alters Wnt receptor clustering and disrupts the spatial regulation of Wnt ligand presentation, leading to dysregulated β-catenin signaling.¹⁴³ This aberrant activation contributes to pathological processes such as fibrosis, chronic inflammation, and stem cell exhaustion.¹⁴⁴ Wnt/β-catenin signaling modulates the mechanical integrity of adherens junctions by regulating E-cadherin and α-catenin interactions, thereby influencing cytoskeletal organization and mechanical resilience of aging tissues.¹⁴⁵

Mechanosensing-based regulation within diseased or aged cells involves the reprogramming of Wnt-related mechanosensors such as LRP5/6 and Frizzled.¹⁴⁶ Modifying the expression or localization of these receptors alters the ability of cells to detect and respond to ECM stiffness, allowing the restoration of homeostatic signaling thresholds.¹⁴⁷ Biomaterials engineered to modulate Wnt signaling, such as Wnt-binding hydrogels and stiffness-tunable scaffolds, have shown potential in directing stem cell fate and enhancing tissue regeneration in aged microenvironments.¹⁴⁸ In drug delivery applications, nanoparticles functionalized with Wnt inhibitors or activators can be designed to release their cargo in response to matrix tension or compression, enabling precise spatial and temporal control of Wnt signaling in fibrotic or degenerative tissues.¹⁴⁹

C. mTOR pathway

The mTOR pathway is the central regulator of cell growth,¹⁵⁰ metabolism,¹⁵⁰ and survival¹⁵¹ and integrates signals from nutrients, growth factors, and cellular energy status to control various cellular processes.¹⁵² Mechanistic target of rapamycin complex 1 (mTORC1) is sensitive to rapamycin and regulates cell growth and metabolism, whereas mechanistic target of rapamycin complex 2 (mTORC2) is involved in regulating cytoskeleton and cell survival.¹⁵³ mTORC1 is activated by the small GTPase Ras homolog enriched in the brain (Rheb), which is regulated by tuberous sclerosis complex 1/2.¹⁵⁴ In the presence of growth factors, the phosphoinositide 3 kinase (PI3K)/AKT pathway phosphorylates and inhibits the tuberous sclerosis complex 2, leading to Rheb activation and subsequent mTORC1 activation.¹⁵⁵

Amino acids activate mTORC1 through RAG GTPases, which recruit mTORC1 to the lysosomal surface where they interact with Rheb.¹⁵³ Activated mTORC1 phosphorylates several downstream targets, including S6 kinase and eukaryotic initiation factor 4E-binding protein-1.¹⁵⁶ S6 kinase phosphorylation promotes protein synthesis by enhancing the translation of mRNAs involved in ribosome biogenesis and cell growth.¹⁵⁷ mTORC2 is activated by growth factors and involved in AKT phosphorylation at Ser473, which is required for complete AKT activation.^158,159 mTORC2 also phosphorylates other protein kinase A, G, and C family kinases, such as serum and glucocorticoid regulated kinase 1 and protein kinase C, which regulate the cytoskeleton and cell survival.¹⁵⁵ mTORC1 negatively regulates autophagy by phosphorylating and inhibiting Unc 51-like kinase 1 complex. Under nutrient-rich conditions, mTORC1 suppresses autophagy, whereas nutrient deprivation leads to the inhibition of mTORC1 and activation of autophagy, enabling the cells to recycle macromolecules and maintain energy homeostasis.¹⁵³

Mechanical stimulation regulates the activation of mTORC1 through the insulin-like growth factor 1 and PI3K/AKT pathways, as the amount of calcium inflow through stretch-activated channels varies.^160–164 mTORC1 inhibition enhances autophagy, thereby promoting cellular homeostasis and mitigating age-related dysfunction.¹⁶⁵ Reduced mTORC1 activity is also associated with decreased chronic inflammation by limiting the production of pro-inflammatory cytokines, highlighting its potential role in combating inflammaging.¹⁶⁶

The mTOR pathway integrates mechanical signals with metabolic and growth-related cues to regulate protein synthesis, autophagy, and mitochondrial function.¹⁵⁰ mTORC1 is primarily activated by mechanical loading through mechanosensitive ion channels, focal adhesion complexes, and the PI3K/AKT pathway.¹⁶⁷ Compression and tension induce calcium influx via stretch-activated channels, which in turn modulate AKT phosphorylation and promote mTORC1 activation.¹⁶⁷ This activation enhances anabolic processes and cell growth but, when persistent, can also contribute to aging-associated cellular hypertrophy and senescence.¹⁶⁸

In aged tissues, chronically elevated ECM stiffness and loss of elasticity lead to sustained mTORC1 activation, impairing autophagy and exacerbating mitochondrial dysfunction.¹⁶⁹ These effects result in increased ROS production and accumulation of damaged proteins, contributing to tissue degeneration and inflammaging.¹⁷⁰ Inhibiting mTORC1 activity through mechanical unloading or soft ECM environments restores autophagy, enhances metabolic homeostasis, and improves cellular resilience.¹⁷¹

Mechanical control of mTOR-related mechanosensing in diseased aged cells includes targeting stretch-activated channels and upstream activators such as integrins and FAK.¹⁷² Modulating these sensors can recalibrate the sensitivity of the mTOR pathway sensitivity to mechanical input.¹⁷³ Engineering approaches utilizing viscoelastic hydrogels, 3D culture systems with gradient stiffness, and nanoparticle delivery of mTOR modulators have demonstrated success in reestablishing mTOR signaling balance.¹⁷⁴ Mechanoresponsive nanoparticles that release rapamycin in tension-rich environments allow localized mTOR inhibition, improving therapeutic outcomes in fibrotic or inflamed tissues.¹⁷⁵

D. The Janus kinase (JAK)/signal transducer and activator of transcription (STAT) pathway

Defective JAK/STAT signaling has been linked to chronic inflammation and decreased cellular responsiveness, which are hallmarks of cardiovascular aging.¹⁷⁶ Impairment of this pathway contributes to the deterioration of cardiovascular function with age.¹⁷⁷ The JAK/STAT pathway is more active in the adipose tissue of aging animals than in the tissues of younger animals, as well as in senescent cells rather than in non-senescent cells.¹⁷⁸ This increased activation is associated with increased inflammation and metabolic dysfunction, indicating a direct link between JAK/STAT signaling and aging.¹⁷⁹ This capability is crucial for maintaining cellular homeostasis and function and tends to decline with age.¹⁷⁰

The JAK/STAT pathway is influenced by mechanical forces such as shear stress and tissue stiffness, which are prevalent during aging. Disruption of this mechanosensitive pathway contributes to increased inflammation and metabolic dysfunction—strong indicators of cardiovascular aging and tissue degeneration.¹⁷⁹ In senescent cells and aged adipose tissue, heightened JAK/STAT activation under mechanical imbalance exacerbates pro-inflammatory responses and impairs cellular homeostasis.³ Focusing on the mechanobiological aspects of the JAK/STAT pathway may help in the restoration of tissue function and treatment of aging-associated diseases.¹⁷⁹

The JAK/STAT signaling cascade is highly responsive to biomechanical forces such as ECM deformation, matrix stiffening, and shear stress.¹⁸⁰ Mechanical signals modulate the spatial organization and activation of JAKs at focal adhesion sites, facilitating STAT phosphorylation and nuclear translocation.¹⁸¹ Shear-induced mechanical strain activates JAK2 and STAT3 in endothelial cells, promoting pro-inflammatory cytokine expression and vascular remodeling.¹⁸²

In aged ECM environments, which are characterized by fibrotic remodeling and increased stiffness, JAK/STAT signaling becomes chronically activated, leading to excessive secretion of SASP factors and persistent inflammation.¹⁸³ The interplay between integrin-mediated mechanosensing and JAK/STAT activation contributes to immune dysregulation and senescence propagation in surrounding cells.¹⁸⁴ Thus, this mechanotransduction pathway thereby links age-related matrix changes to systemic inflammaging.¹⁸⁵

Modulation of mechanosensing elements upstream of JAK/STAT, such as integrin FAK complexes and the tension-responsive actin cytoskeleton, has emerged as a strategy to regulate pathway activity in diseased aging cells.¹⁸⁶ Targeting the mechanical inputs that initiate STAT phosphorylation helps to normalize inflammatory responses.³ From a therapeutic standpoint, mechanical modulation of JAK/STAT activity through soft substrates or cyclic mechanical conditioning has shown promise in reducing inflammatory gene expression and restoring homeostasis.¹⁸⁷ Liposomal nanoparticles encapsulating JAK inhibitors are also being developed to respond to ECM mechanical states, allowing targeted suppression of inflammation in stiffened, aged tissues.¹⁸⁸

E. The extracellular signal-regulated kinase (ERK) 1/2 pathway

The ERK1/2 pathway is activated when growth factors bind to receptor tyrosine kinases, thus triggering receptor dimerization and autophosphorylation.¹⁸⁹ ERK1/2 can phosphorylate cytoplasmic substrates and regulate processes, such as cytoskeletal rearrangement and cell migration.¹⁹⁰ The ERK1/2 pathway is tightly regulated by various mechanisms to prevent its overactivation.¹⁹¹ Dual-specificity phosphatases dephosphorylate ERK1/2, thereby inactivating it and terminating its signal. In the context of aging, the ERK1/2 pathway drives the senescent phenotype in response to senescence-induced stimuli.¹⁹² The ERK1/2 pathway is involved in the regulation of autophagy, a process that declines with age and contributes to the accumulation of damaged cellular components.¹⁹³ Inhibition of sirtuin1, a longevity-associated protein, reduces Ras/ERK1/2 pathway activation, suggesting a complex interplay between these signaling networks in the regulation of aging. Because of its pivotal role in aging and cellular senescence, the ERK1/2 pathway is a potential target for therapeutic interventions to mitigate age-related cellular dysfunction and promote healthy aging.¹⁹⁴

Mechanical signals initiate receptor tyrosine kinase activation, propagate downstream ERK1/2 signaling, and bridge the mechanical and biochemical pathways.^3,195 Increased tissue stiffness owing to ECM remodeling amplifies mechanical inputs, thereby causing hyperactivation of the ERK1/2 pathway.³ Mechanical stress-induced ERK1/2 activation exacerbates senescence and dysfunction of fibroblasts and endothelial cells.¹⁹⁶

The ERK1/2 pathway is a crucial mediator of cellular responses to mechanical and biochemical stimuli, playing roles in proliferation, differentiation, and senescence.¹⁹⁷ Mechanical forces, such as matrix stretching and compression, activate ERK1/2 via receptor tyrosine kinases and integrin FAK signaling.¹⁹⁸ These stimuli initiate the Ras-Raf-MEK cascade, leading to ERK1/2 phosphorylation and downstream nuclear transcriptional responses.¹⁹⁹

In aged tissues, ECM stiffening increases the mechanical load transmitted through focal adhesions, resulting in ERK1/2 hyperactivation.²⁰⁰ This chronic signaling promotes fibroblast senescence, enhances the expression of matrix-degrading enzymes, and disrupts tissue homeostasis. Furthermore, elevated ERK1/2 activity has been linked to impaired autophagy, a hallmark of aging cells.²⁰¹

Mechanosensing in aged cells can be reprogrammed by targeting upstream ERK activators such as syndecans and integrin-linked kinases, which respond to ECM tension.²⁰² Inhibiting aberrant force transmission through these sensors reduces ERK1/2 overactivation.²⁰³ Mechanoadaptive materials, such as dynamic stretch devices and elasticity-controlled hydrogels, have been utilized to fine-tune ERK1/2 signaling.²⁰⁴ Nanocarrier systems that deliver ERK inhibitors or MAPK pathway modulators are being designed to respond to mechanical stimuli such as matrix tension, which should ensure precise inhibition of hyperactive pathways in stiffened, aging tissues.²⁰⁵

F. The Hippo/YAP pathway

The Hippo pathway involves a series of molecular events that transmit signals from the cell membrane to the nucleus, ultimately regulating gene expression.²⁰⁶ This pathway is initiated by various upstream signals, including cell–cell contact, mechanical stress, and ECM stiffness.²⁰⁷ These signals activate the core kinase cascade of the Hippo pathway, starting with the mammalian sterile 20-like protein kinases 1 and 2.²⁰⁸ In association with the adaptor protein Mps one binder 1, activated large tumor suppressor 1/2 kinases that phosphorylate the transcriptional coactivators YAP and TAZ.²⁰⁹ YAP/TAZ phosphorylation causes it to become sequestered in the cytoplasm by binding to 14-3-3 proteins, preventing their translocation to the nucleus and subsequent transcriptional activity.²¹⁰ This transcriptional activity is essential for maintaining organ size and supporting tissue regeneration.²⁰⁷ Overall, the Hippo/YAP pathway plays a notable role in maintaining tissue regeneration and stem cell function.²¹¹

Age-related decline in YAP/TAZ activity has been linked to reduced regenerative capacity and increased tissue degeneration, particularly in the skin, where it regulates both epidermal and dermal aging.²¹² The Hippo/YAP pathway is highly sensitive to mechanical cues like ECM stiffness, cell density, and tensile forces, which regulate YAP/TAZ nuclear localization and transcriptional activity.²⁶ Mechanical stresses such as cyclic stretching or substrate stiffness activate YAP/TAZ by inhibiting the phosphorylation cascade of the Hippo pathway. For example, stiff ECM conditions enhance the nuclear activity of YAP/TAZ, thereby promoting cellular proliferation and tissue growth.²¹³ Soft ECM environments or mechanical unloading reduce YAP/TAZ activity, which is crucial for maintaining stem cell quiescence and preventing excessive proliferation.²¹⁴ During aging, chronic mechanical stress and ECM stiffening disrupt YAP/TAZ activity, thereby contributing to tissue fibrosis and the loss of regenerative potential.⁷

The Hippo/YAP signaling axis is a master regulator of mechanotransduction, translating mechanical cues from the ECM and cytoskeleton into transcriptional programs that control cell proliferation, organ size, and regeneration.²¹⁵ In mechanically relaxed environments, the Hippo kinase cascade is activated, leading to YAP/TAZ phosphorylation and cytoplasmic retention. Mechanical tension, actomyosin contraction, and ECM stiffening inhibit Hippo kinases, allowing YAP/TAZ to accumulate in the nucleus and driving gene expression.²¹⁶

In aged tissues, sustained ECM stiffening and elevated cytoskeletal tension result in prolonged YAP activation, promoting fibrosis, cellular senescence, and loss of tissue plasticity.²¹⁷ YAP/TAZ dysregulation contributes to altered chromatin organization, impaired DNA repair, and stem cell exhaustion.²¹⁸ Controlled mechanical stimulation, such as pulsatile flow, cyclic stretching, or hydrogel-based soft environments, can restore YAP activity to regenerative levels.²¹⁴

Reprogramming mechanosensors that regulate the Hippo/YAP axis, including cadherins, α-catenin, and LINC proteins, constitutes a strategy to modulate this pathway in aged or fibrotic tissues.²¹⁹ Targeted interventions can reset nuclear tension thresholds and restore proper YAP/TAZ shuttling.⁹ Engineered biomaterials with tunable stiffness and ligand presentation have been designed to modulate YAP nuclear localization and activity.¹⁴⁸ These materials support the reactivation of regenerative transcriptional programs while suppressing fibrotic signaling.²²⁰ Additionally, nanoparticles targeting YAP TEAD interactions or delivering YAP/TAZ small interfering RNAs (siRNAs) can be activated in response to mechanical tension, offering spatiotemporal control of mechanotransduction in aging microenvironments²²¹ (Fig. 2).

FIG. 2. — The effect of shear stress and substrate stiffness on TAZ/YAP signaling and cellular morphology. (a) Representative immunofluorescence images showing DAPI (blue), TAZ (green), and F-actin (red) in control and shear stress conditions. (b) Quantification of TAZ subcellular localization in control and shear stress conditions. (c) Quantitative reverse transcription polymerase chain reaction (qRT-PCR) analysis showing relative fold induction of CTGF and Cyr61 in control and shear stress conditions. (d) Representative images of mineralized nodules in control and shear stress conditions, stained with Alizarin Red S. (e) qRT-PCR analysis of osteogenic marker genes (TAZ, Runx2, DLX5, Msx2) under control and shear stress conditions. Reproduced with permission from Kim *et al.*, PLoS One 9, e92427 (2014). Copyright 2014 Authors, licensed under a Creative Commons Attribution (CC BY) license. (f) Immunofluorescence staining of Phalloidin (yellow) and YAP (white) in cells cultured on 5 and 29 kPa substrates under control and Talin 2 shRNA conditions. (g) Schematic representation of cell morphology changes in control and Talin 2 shRNA conditions. Reproduced with permission from Elosegui-Artola *et al.*, Cell **171**, 1397 (2017). Copyright 2017 Elsevier.

IV. MECHANOMEDICINE: DISEASE-SPECIFIC TARGETED THERAPY FOR CELLULAR REJUVENATION

A. Chronic inflammation

Inflammaging impairs tissue structure and function and decreases regenerative capacity.²²² The accumulation of senescent cells within tissues elevates the secretion of SASP, a mixture of pro-inflammatory cytokines, chemokines, and proteases, which destroys the microenvironment and accelerates age-related pathologies, such as cardiovascular diseases and osteoarthritis (OA).²²³ Age-related ECM stiffening enhances integrin-mediated mechanosignaling, activating FAK, RhoA/ROCK, and downstream NF-κB, which together promote the SASP.²²⁴ This mechanotransduction cascade reinforces chronic pro-inflammatory loops by promoting the secretion of IL-6, IL-1β, and TNF-α, and drives further matrix degradation via MMP.²²⁵ This dismantles the structure and function of tissues and impairs their regenerative abilities.²²⁶

ECM-targeting interventions aim to restore the biomechanical properties of aging tissues by employing biomaterial-based scaffolds that mimic the native ECM environment.²²⁷ These scaffolds provide structural support and biochemical cues that promote cellular rejuvenation.²²⁸ Enzymatic degradation of fibrotic ECM components, such as collagen and elastin crosslinks, can alleviate age-related tissue stiffness and improve mechanotransduction-based signaling.²²⁹

Mechanotransduction-targeted drug delivery focuses on modulating focal adhesion signaling, which plays a crucial role in cellular aging.²³⁰ Nanoparticles engineered to regulate integrin-mediated mechanosensing can selectively enhance or inhibit FAK activity, restoring proper mechanotransduction and preventing senescence-associated signaling cascades.²³¹ These approaches allow for precise control over the mechanobiological pathways involved in tissue regeneration and cellular repair.²³²

Direct cellular reprogramming via mechanomodulation of cytoskeletal tension and nuclear mechanics offers an innovative strategy for reversing cellular senescence.²⁵ By modulating actin cytoskeletal tension and nuclear stiffness, it is possible to influence YAP/TAZ activity, chromatin remodeling, and mitochondrial function, ultimately restoring a youthful cellular phenotype.²³³ Emerging technologies such as substrate stiffness tuning and dynamic mechanical loading have demonstrated significant potential in resetting cellular mechanotransduction programs.¹⁷

Mechanomedical approaches aim to reverse these effects by modulating ECM stiffness and reestablishing mechanical homeostasis.³ Polyethylene glycol-based soft hydrogel scaffolds reduce nuclear stress and downregulate NF-κB signaling in senescent immune cells.²³⁴ Nanoparticles encapsulating FAK inhibitors or YAP/TAZ siRNA can be delivered using ECM tension-sensitive release mechanisms, such as MMP cleavable linkers.²³⁵ These interventions allow spatially restricted, mechanically triggered immunomodulation in fibrotic or inflamed tissues, restoring balance to innate and adaptive immunity.²³⁶

These comprehensive approaches, including therapies targeting cellular senescence, efferocytosis, and mitochondria, offer promising avenues for mitigating chronic inflammation, enhancing tissue function, and slowing down the progression of age-related diseases²³⁷ (Fig. 3).

FIG. 3. — Effects of Nestin (NES) knockdown on cellular senescence, inflammatory cytokine expression, and nuclear architecture. (a) NES knockdown in A549 and H1299 cells induces an increase in senescence markers, as shown by SA-β-gal staining. (b) and (c) Increased mRNA expression levels of IL-6 and IL-8 in NES-knockdown A549 and H1299 cells. (d) Altered distribution of lamin B and H3K9me3 in NES-knockdown A549 and H1299 cells. Reproduced with permission from Zhang *et al.*, Nat. Commun. 9, 3613 (2018). Copyright 2018 Authors, licensed under a Creative Commons Attribution (CC BY) license. (e) Quantification of SA β-galactosidase-positive cells in control and NES knockdown conditions. (f) Relative senescence-associated secretory phenotype (SASP) expression in control and NES knockdown conditions. (g) Representative fluorescence images of nuclear envelope integrity under different conditions (V: Vehicle, D: Drug, Q: Quiescence, D + Q: Drug + Quiescence). (h) Quantification of fluorescence intensity under different conditions. Reproduced with permission from Zhu *et al.*, Aging Cell 14, 644–658 (2015). Copyright 2015 Authors, licensed under a Creative Commons Attribution (CC BY) license.

B. Cancer

Aging and cancer are intricately linked through various biological mechanisms that contribute to the increased incidence of cancer in aging adults.

Therapeutic strategies targeting the interplay between aging and cancer focus on mitigating inflammation, eliminating senescent cells, and enhancing immune responses.²³⁸ Anti-inflammatory therapies, such as IL-1β inhibitors and COX-2 blockers, reduce inflammation-driven tumorigenesis by suppressing pro-inflammatory pathways.^239,240 Certain compounds can target and remove senescent cells, reduce their pro-tumorigenic secretome, and promote the restoration of tissue homeostasis.²⁴¹ Advanced drug delivery systems, including nanoparticles and lipid-based carriers, can enhance the specificity and efficacy of chemotherapeutics, while minimizing systemic toxicity.^242,243 ECM remodeling strategies targeting tumor-associated stiffness disrupt mechanotransduction pathways and impair cancer cell proliferation and metastasis.²⁴⁴ In aged tissues, the TME becomes mechanically dysregulated due to increased collagen cross-linking, enhanced matrix stiffness, and elevated actomyosin contractility in cancer-associated fibroblasts.²² These changes activate integrin FAK-Src-YAP/TAZ signaling cascades, leading to epithelial–mesenchymal transition, metabolic reprogramming, and immune evasion.⁸³ Mechanically driven changes in nuclear morphology further disrupt chromatin topology and DNA repair capacity in cancer cells.²⁷

Mechanomedical interventions target these abnormalities by combining ECM-modifying enzymes with mechano-adaptive biomaterials.²⁴⁵ For instance, MMP-sensitive nanoparticles loaded with paclitaxel are preferentially activated in fibrotic, stiff regions of tumors.²⁴⁶ Hydrogel scaffolds presenting RGD integrin ligands in spatial gradients can also normalize mechanotransduction and reduce YAP-driven tumorigenesis.²⁴⁷ Finally, mechanical softening of the TME using viscoelastic fillers suppresses CAF activation and enhances responsiveness to immune checkpoint blockade, representing a synergy between mechanobiology and immune oncology.²⁴⁸

C. Immune disorders

Aging-induced ECM remodeling alters immune cell mechanosensing through increased stiffness and disrupted topography.²⁴⁹ This impairs integrin-mediated signaling and alters the actin cytoskeleton, reducing T-cell activation thresholds and diminishing B-cell germinal center responses.²⁵⁰ Chronic mechanical stress activates the JAK/STAT and NF-κB pathways, fueling immunosenescence and autoimmunity.²⁵¹ Inflammaging perpetuates immune dysfunction by persistently activation innate immune responses and the secretion of pro-inflammatory cytokines such as IL-6, IL-1β, and TNF-α.⁹⁸ This inflammatory state disrupts immune homeostasis and contributes to an increased susceptibility to infections, autoimmune diseases, and cancer.²⁴⁰ In addition to these systemic changes, aging directly affects immune cells, leading to functional decline and impaired responses to pathogens.⁹⁸

Moreover, senescent immune cells accumulate and secrete SASP factors, including chemokines and matrix-degrading enzymes, creating a pro-inflammatory microenvironment that exacerbates immune dysregulation and tissue damage.²⁵² In aging immune cells, overproduction of ROS impairs signal transduction and cellular function.²⁴³ Glycolytic reprogramming alters the metabolic profile of aged immune cells, thereby reducing their ability to mount effective responses to infections and tissue damage.²⁵³

Mechanomedical strategies involve restoring mechanical elasticity in immune niches via decellularized ECM scaffolds with defined viscoelastic profiles.²⁵⁴ Biomaterials coated with intercellular adhesion molecule 1 and vascular cell adhesion molecule 1 on compliant substrates can enhance T-cell mechanotransduction and cytokine sensitivity.²⁵⁵ Mechanically responsive polymeric nanoparticles delivering JAK inhibitors or IL-10 can also modulate local immune responses in fibrosis or aged lymphoid tissues.²⁵⁶ To summarize, these approaches reduce inflammation while preserving antigen-specific immunity, reprogramming immunological aging through physical microenvironmental control.²⁵⁷

Therapeutic strategies to counteract these effects include mitigating inflammation, enhancing immune function, and restoring immune homeostasis.²⁵⁸ Adjuvants, such as MF59 and AS03, enhance vaccine efficacy in aging adults by boosting antigen presentation and innate immune activation, leading to improved protection against infections.²⁵⁹ For example, the Shingrix vaccine, which contains an AS01 adjuvant, significantly improves protection against shingles in aging populations compared with traditional vaccines.²⁶⁰ Anti-inflammatory therapies, such as canakinumab, an IL-1β inhibitor, effectively reduce systemic inflammation and improve immune resilience.²⁶¹

Nanoparticle-based drug delivery systems offer precise therapeutic options by enhancing the specificity and minimizing off-target effects.²⁶² For instance, lipid nanoparticles delivering siRNA against TNF-α have shown promise in reducing inflammation in preclinical models.²⁶³ By integrating these approaches, therapeutic interventions can effectively address age-related declines in immune function; reduce the risk of infections, autoimmune diseases, and chronic inflammation; and promote overall immune resilience and health in aging adults.²⁶⁴

D. Other diseases

Aging is a critical determinant in the progression of numerous diseases beyond those conventionally linked to it.²⁶⁵ Mechanosensing via αvβ6 integrins, FAK, and YAP/TAZ enhances SMAD2/3 nuclear localization, creating a positive feedback loop.²⁶⁶ In OA, chondrocyte mechanotransduction through TRPV4 and integrins is impaired due to cartilage stiffening and altered pericellular matrix composition, which results in inflammation and degradation of the ECM.²⁶⁷ Idiopathic pulmonary fibrosis (IPF) is a prime example of an age-induced transcriptional abnormality that causes continuous activation of the fibroblasts, leading to excessive ECM accumulation and alveolar damage.²⁶⁸ Targeting TGF-β signaling using small-molecule inhibitors, such as pirfenidone and nintedanib, has shown clinical efficacy in slowing IPF progression by mitigating fibroblast activation and collagen deposition.²⁶⁹

The accumulation of lipofuscin and drusen deposits in the retinal pigment epithelium triggers chronic inflammation and complement activation, leading to photoreceptor death.²⁷⁰ Oxidative stress driven by mitochondrial dysfunction exacerbates these processes, highlighting the role of aging in AMD pathogenesis.⁶¹ Therapies targeting the complement cascade, such as the use of anti-C5 monoclonal antibodies, have shown promise in reducing inflammation and slowing disease progression.²⁷¹

Cardiovascular aging involves increased vascular stiffness and pulse pressure, which trigger mechanosensitive ERK1/2 and RhoA/ROCK pathways in smooth muscle and endothelial cells.²⁷² These changes reduce nitric oxide bioavailability and promote arterial remodeling.²⁷³ Advanced therapies, including lipid-lowering agents such as PCSK9 inhibitors and anti-inflammatory drugs such as colchicine, aim to reduce the atherosclerotic burden and improve vascular health.²⁷⁴ In addition, regenerative approaches, including endothelial progenitor cell therapy, have been explored as a means of restoring vascular integrity and promoting angiogenesis.²⁷⁵ Aging is a pivotal factor that contributes to insulin resistance and type 2 diabetes.²⁷⁶ Cellular senescence in pancreatic β-cells and adipocytes impairs insulin secretion and sensitivity, whereas inflammaging exacerbates metabolic dysregulation.²⁷⁷ Therapies targeting senescence-associated pathways, such as mTOR inhibitors like rapamycin, may improve insulin sensitivity and delay the onset of type 2 diabetes.²⁷⁸ Dietary interventions, including intermittent fasting and caloric restriction, are also effective in mitigating age-related metabolic decline.²⁷⁹

Mechanomedical solutions include stretchable stents with tunable mechanical compliance that buffer pressure fluctuations and reduce vascular mechanostress.²⁸⁰ In IPF, inhalable nanocarriers that are responsive to high-tension ECM can selectively deliver antifibrotic agents in stiffened alveolar regions.²⁸¹ In OA, cartilage adhesive hydrogels delivering TRPV4 agonists restore anabolic signaling.²⁸² These targeted interventions reverse pathologic mechanotransduction in aging tissues and reestablish homeostatic mechanical signaling essential for organ integrity.¹

OA exemplifies the impact of aging on musculoskeletal health.²⁸³ Chondrocyte senescence and ECM degradation lead to thinning of the cartilage and joint inflammation; furthermore, oxidative stress accelerates these degenerative changes.²⁸⁴ Current therapeutic approaches focus on alleviating symptoms and halting disease progression. Intra-articular injections of hyaluronic acid and corticosteroids provide symptomatic relief, whereas emerging therapies, such as MSC-derived exosomes, show promise for promoting cartilage repair and reducing inflammation²⁸⁵ (Figs. 4 and 5).

FIG. 4. — The effect of ECM stiffness and HDAC3 expression on osteoarthritis (OA) progression. (a) Aging markers (DAPI, p16, p21) observed in cartilage tissue under increased ECM stiffness. Reproduced with permission from Fu *et al.*, Bone Res. 12, 32 (2024). Copyright 2024 Authors, licensed under a Creative Commons Attribution (CC BY) license. (b) Immunofluorescence staining shows alterations in F-actin (red) and vinculin (green) localization, along with nuclear DAPI staining (blue), demonstrating cytoskeletal reorganization under different conditions. (c) Quantification of F-actin fluorescence intensity reveals increased cytoskeletal tension in both young and aged cells following TGFβ1 treatment. (d) Vinculin fluorescence intensity indicates focal adhesion remodeling, highlighting differences between young and aged cells. Reproduced with permission from Zhu *et al.*, Sci. Rep. 8, 2668 (2018). Copyright 2018 Authors, licensed under a Creative Commons Attribution (CC BY) license.

FIG. 5. — OA progression linked to ECM stiffness and HDAC3-related protein alterations. (a) HDAC3 staining in cartilage sections from control and OA models. (b) and (c) The percentage of HDAC3-positive cells was significantly higher in OA samples compared to controls, correlating with the severity of cartilage degeneration. OARSI scoring further highlights the progression of OA, showing significant increases in degeneration from control to moderate and severe conditions. Reproduced with permission from Fu *et al.*, Bone Res. 12, 32 (2024). Copyright 2024 Authors, licensed under a Creative Commons Attribution (CC BY) license. (d) PDK1 inhibition reverses cellular senescence in human dermal fibroblasts by modulating the mTOR and NF-κB pathways, restoring the morphological and functional characteristics of youthful cells. Reproduced with permission from Proc. Natl. Acad. Sci. **117**, 31535 (2020). Copyright 2020 National Academy of Sciences.

V. ENGINEERING APPLICATIONS OF MECHANOBIOLOGICAL THERAPIES

A. Mechanical modulation for cellular rejuvenation

Mechanical modulation is pivotal in cellular rejuvenation as it alters cellular architecture and enhances functions to counteract aging.²⁸⁶ Mechanical stretching activates the Nrf2 antioxidant pathway, reducing oxidative stress, and preserving mitochondrial integrity.²⁸⁷ Dynamic mechanical loading has been shown to increase ECM turnover by activating MMPs, facilitating the removal of damaged proteins and promoting tissue elasticity.³ These interventions mitigate ECM stiffening, a hallmark of aging, thereby improving cellular function.²⁸⁸ Mechanical stimuli such as stretching and compression reorganize cytoskeletal structures, activate ion channels, and regulate intracellular signaling pathways, driving key cellular processes like differentiation and survival.²⁸⁹

Another approach focuses on optimizing drug delivery in aging ECM environments, where increased fibrosis and stiffness hinder therapeutic efficacy.²⁹⁰ Nanoparticle-based mechanosensitive carriers enable targeted drug release in response to mechanical cues, improving bioavailability in fibrotic tissues.²⁹¹

Mechanosensitive ion channels, such as piezo1 and transient receptor potential vanilloid 4, are key mediators of cellular responses to mechanical stimuli. They regulate calcium influx and activate downstream signaling pathways critical for cytoskeletal remodeling and cellular rejuvenation.²⁴ These mechanomodulation strategies provide a foundation for advanced applications such as nanoparticle-based therapies, which have the potential to further enhance the precision of cellular and tissue rejuvenation.²⁹¹ Physical design approaches for biomaterials are increasingly being leveraged to promote cellular rejuvenation by modulating mechanical signals. In mechanobiology, engineered biomaterials are designed to replicate the physical properties of the ECM—such as stiffness, elasticity, and topography—thereby mimicking the natural mechanical cues of the ECM, which cells recognize and respond to through mechanotransduction pathways. For example, adjusting ECM stiffness through the design of biomaterials can restore stem cell differentiation by activating the YAP/TAZ signaling pathways, which are critical for cellular rejuvenation. The mechanical stimulation provided by these biomaterials leads to calcium influx, activating downstream signaling pathways that enhance cytoskeletal remodeling and promote cellular rejuvenation. This process is critical for reversing age-related cellular dysfunction, particularly in tissues with altered ECM properties due to aging.²⁹¹ Oscillatory mechanical forces enhance stem cell differentiation by upregulating YAP/TAZ activity, which translocates to the nucleus and promotes the expression of regenerative genes.⁴³ By integrating mechanical modulation with advanced biomaterials such as hydrogel scaffolds, precise control over mechanical forces is achieved, ensuring long-term tissue regeneration.²⁹²

A comprehensive analysis of ECM elasticity and topography provides insights into how material-based cues influence cellular function in mechanobiology. Cells respond to changes in ECM stiffness by altering both their mechanical and biochemical signaling pathways, which in turn affects their behavior. For instance, modifying ECM stiffness can activate mechanosensitive ion channels, including Piezo1 and TRPV4, which regulate calcium influx and drive the downstream signaling pathways essential for cellular rejuvenation. These mechanical cues also enhance cellular reprogramming by promoting the activation of stem cells, improving mitochondrial function, and restoring youthful gene expression profiles. By manipulating ECM elasticity, cells can be reprogrammed to exhibit characteristics of younger, more regenerative states, which is essential for reversing aging processes and promoting tissue regeneration.²⁹²

B. Nanoparticles in mechanobiological therapies

Nanoparticles represent a sophisticated engineering strategy for mitigating mechanobiological changes in aging tissues.²⁹³ These systems operate by making targeted modifications of the ECM, enhancing drug delivery efficacy within aged ECM microenvironments, and precisely modulating intracellular mechanosensitive signaling pathways.²³⁶ ECM-targeting nanoparticles focus on remodeling the aged microenvironment by delivering MMP-based therapeutics to degrade excessive ECM components, thereby restoring tissue elasticity.²⁹⁴ Hybrid nanoparticles combining organic and inorganic components can further enhance ECM interactions and promote tissue repair,²⁹⁵ where nanoparticles were engineered to be small enough to penetrate this rigid matrix. By loading chemotherapeutic agents into these nanoparticles, the study demonstrated that these carriers could facilitate deeper tissue penetration, resulting in enhanced therapeutic outcomes.²⁹⁵ This approach specifically addresses the mechanobiological challenge posed by ECM stiffness, as the nanoparticles can not only traverse, but also remodel the ECM. This remodeling process is key to enhancing cellular rejuvenation within the tumor microenvironment.²⁹⁵

Nanoparticles play a foundational role in mechanobiological therapies by providing unparalleled precision for drug delivery and tissue regeneration.²⁹⁶ These scaffolds have been carefully engineered with controlled topographies and stiffness properties that provide specific mechanical cues to influence stem cell behavior.²⁹⁶ By precisely designing these nanomaterial scaffolds, stem cells could be directed to regenerate tissues by responding to the mechanosensory signals embedded in the materials.²⁹⁶ This mechanobiological approach not only promotes cellular rejuvenation but also creates an optimal environment for enhanced tissue regeneration, closely mimicking the natural ECM properties that are vital for cellular health.²⁹⁶ These characteristics mean that nanoparticles can be used to treat age-associated diseases and mechanobiological dysfunctions, for which conventional treatments often fall short.²⁹⁷ Lipid-based nanoparticles encapsulating donepezil demonstrated a 45% improvement in BBB permeability and a 30% increase in sustained drug release, resulting in significant cognitive improvements in AD models.²⁹⁸

Nanoparticle-based drug delivery systems can help overcome the challenges of the BBB, a significant hurdle in treating neurodegenerative diseases.²⁶⁰ The BBB, which becomes increasingly permeable during aging, can be targeted using nanoparticles to improve the delivery of therapeutic agents such as antioxidants, mitochondria-targeted drugs, and gene therapies.²⁶⁰ By integrating mechanotransduction into these delivery systems, researchers can fine-tune drug release in response to mechanical cues from the tissue matrix, thereby improving therapeutic outcomes in aging-related neurodegenerative diseases.²⁹⁹ This approach is not only focused on alleviating the symptoms of neurodegenerative diseases but also on counteracting the aging-associated remodeling of the ECM and cellular aging itself.²⁶⁰

Nanoparticle-based drug delivery systems, such as lipid nanoparticles and polymeric hydrogels, improve BBB penetration and enhance drug efficacy in neurological disorders.³⁰⁰ Regenerative therapies using induced pluripotent stem cells and mesenchymal stem cells (MSCs) promote neuronal regeneration and synaptic repair, offering hope for reversing neurodegenerative damage.² In neurodegenerative conditions such as Alzheimer's disease, BBB integrity is compromised due to chronic neuroinflammation and endothelial dysfunction.^260,299 Mechanomedicine approaches that target these physical and biochemical signaling axes using smart nanocarriers or matrix-responsive delivery systems.²⁹⁹

In regenerative medicine, nanoparticles facilitate the localized and sustained delivery of therapeutic agents, promoting tissue repair and regeneration.³⁰¹ Hybrid nanoparticles that integrate organic and inorganic components are advancing dual-functional approaches.³⁰² These nanoparticles deliver drugs with 80% targeting efficiency and enable real-time imaging for therapeutic monitoring, representing a significant advancement in precision medicine.³⁰³ Lipid-based nanoparticles encapsulating small molecules or gene editing tools such as Cas9 ribonucleoproteins have demonstrated the ability to optimize drug delivery by improving penetration in stiffened ECM environments, thereby increasing therapeutic efficacy.³⁰⁴ pH-sensitive nanoparticles, designed to release drugs specifically in the acidic microenvironments of fibrotic or tumor tissues, enhance drug specificity while minimizing systemic toxicity.³⁰⁵ Oncology remains a pivotal area for nanoparticle applications, where targeted delivery reduces systemic toxicity and improves therapeutic outcomes.³⁰⁶ Nanoparticles loaded with chemotherapeutic agents, such as doxorubicin, reduced tumor size by 70% in preclinical models, while demonstrating 50% lower toxicity than standard chemotherapy protocols.³⁰⁷ pH-sensitive nanoparticles designed to release drugs in acidic tumor microenvironments demonstrated a 50% increase in therapeutic efficacy by minimizing off-target effects.³⁰⁸ In fibrotic diseases, MMP-conjugated nanoparticles achieved 60% restoration of tissue elasticity and a 35% reduction in fibrotic markers, showcasing their potential for tissue remodeling and normalization of mechanotransduction pathways.³⁰⁹

Lipid nanoparticles encapsulating Cas9 ribonucleoproteins have achieved a 70% success rate in correcting genetic mutations implicated in familial hypercholesterolemia, highlighting their transformative potential for treating genetic disorders.³¹⁰ Despite these advancements, challenges persist in optimizing long-term biocompatibility and minimizing immune responses.³¹¹ Progress in biodegradable nanoparticles and surface modifications is addressing these concerns, and machine learning algorithms are expediting nanoparticle design, reducing optimization time by up to 40%.³¹² By addressing molecular and cellular dysfunction, nanoparticle-based therapies represent a transformative leap in mechanobiological applications³¹³ (Fig. 6).

FIG. 6. — Therapeutic strategies targeting aging mechanisms and cellular rejuvenation. (a) Time-lapse imaging of cellular responses under different conditions, including normal and TGF-β stimulation at various time points (days 5, 7, 10, 13, 16). Heatmaps represent changes in fluorescence intensity over time. Reproduced with permission from Kim *et al.*, Nat. Mater. 23, 290–300 (2023). Copyright 2023 Authors, licensed under a Creative Commons Attribution (CC BY) license. (b) Representative fluorescence images of cells treated with saline, VPQDs, CaNPs, and VPCaNPs. Nuclei are stained with DAPI (blue), membrane structures with DiD (red), and calcium deposits with Calcein (green). (c) X-ray diffraction (XRD) analysis of VPQDs, CaNPs, and VPCaNPs, displaying their crystalline structures. (d) Histological analysis of tissue samples treated with saline, VPQDs, CaNPs, and VPCaNPs. Reproduced with permission from Zhang *et al.*, Nat. Commun. 15, 6783 (2024). Copyright 2024 Authors, licensed under a Creative Commons Attribution (CC BY) license.

C. Mechanochemical dynamic therapy (MDT)

MDT is an innovative mechanobiological therapy that uses mechanical forces to regulate cellular behavior and tissue dynamics.¹ This therapeutic modality addresses age-associated diseases and mechanobiological dysfunctions by integrating mechanical and chemical signals to restore cellular homeostasis and promote tissue regeneration.³¹⁴ MDT aims to reverse these pathological changes by applying controlled mechanical stimuli to activate specific biochemical pathways and enhance cellular responses to external cues.³¹⁵

In fibrosis models, dynamic mechanical compression applied to the fibrotic lung tissue reduced myofibroblast activation by 50% and restored tissue elasticity by 60%.³¹⁶ These findings highlight the potential of MDT to directly modulate cellular mechanotransduction pathways to achieve therapeutic benefits.⁶ MDT significantly influences the ECM, which undergoes extensive remodeling during aging and disease progression.³¹⁷ By applying oscillatory mechanical forces, MDT enhances the activity of matrix-degrading enzymes, such as MMPs, promoting ECM turnover and reducing stiffness.⁴³ This mechanochemical remodeling of the ECM restores tissue elasticity and reestablishes a supportive microenvironment for cellular function and tissue repair. MDT also improves drug penetration by modulating tumor stiffness and interstitial fluid pressure, enhancing nanoparticle distribution and reducing systemic toxicity.³¹⁸ The stiffness of the tumor ECM often poses a significant barrier to effective drug delivery in glioblastoma treatment, limiting the penetration of conventional therapeutics.³¹⁸ However, drug-loaded nanocarriers have been engineered to improve their ability to navigate through the dense tumor ECM.³¹⁸ By optimizing the size and mechanical properties of these nanoparticles, it is possible to enhance their penetration and deliver chemotherapeutic agents more effectively to tumor cells.³¹⁸ This approach addresses the challenges posed by the rigid ECM, as the nanocarriers are specifically designed to traverse and remodel ECM, improving the efficiency of drug delivery. This can significantly improve therapeutic outcomes, increasing drug accumulation in the tumor by 50% compared to conventional therapies.³¹⁸ This mechanobiological strategy restores cellular function within tumor tissues, ultimately promoting cellular rejuvenation and improving responses to treatment.³¹⁸ This approach has been particularly effective in enhancing chemotherapeutic efficacy and restoring vascular integrity in aged tissues.³¹⁹

MDT enhances the penetration and distribution of chemotherapeutic agents by modulating tumor stiffness and interstitial fluid pressure. In bone tissue engineering, cyclic mechanical loading of MSC-seeded scaffolds at 1 Hz increased osteogenic differentiation markers such as alkaline phosphatase activity by 50% and calcium deposition by 60% over 3 weeks.³²⁰ MSCs are critical for tissue regeneration, and their differentiation can be significantly influenced by environmental mechanical properties.³²⁰ Scaffolds designed with engineered elasticity and topography can enhance the osteogenic differentiation of MSCs, thereby contributing to cellular rejuvenation.³²⁰ When MSCs were cultured on soft scaffolds with a Young's modulus of approximately 2 kPa, calcium signaling was activated, promoting their differentiation into osteogenic cells.³²⁰ This mechanotransduction process was pivotal for restoring the differentiation capacity of the stem cells, which is essential for tissue regeneration. Osteogenic markers increased by 30% compared to cells grown on stiffer substrates, demonstrating how mechanical cues in the form of scaffold stiffness can directly influence cellular rejuvenation.³²⁰ This approach underscores the importance of mechanobiology in guiding stem cell fate and enhancing tissue regeneration, making it a powerful tool for therapeutic strategies aimed at rejuvenating aging tissues.³²⁰ Similarly, in cardiac tissue repair, MDT utilizing pulsatile mechanical stretch improved the alignment and contractile function of engineered cardiac patches, enhancing their integration with the host myocardium and restoring 45% of the baseline cardiac output in preclinical models of myocardial infarction³²¹ (Fig. 7).

FIG. 7. — Cellular rejuvenation strategy. Molecular mechanisms—including antioxidant and anti-inflammatory pathways, metabolic energy production, mTOR signaling, and nanoparticle-CRISPR-Cas9-based therapies—are depicted. The TLR2-Nrf2 and CD163-Nrf2 pathways promote tissue regeneration by reducing oxidative stress and modulating anti-inflammatory responses. Glucose metabolism through glycolysis, the TCA cycle, and alcohol fermentation optimize energy production and NAD⁺ synthesis. mTORC1 and mTORC2 regulate cell growth and survival through amino acid signaling, whereas nanoparticles enhance targeted delivery, and CRISPR-Cas9 restores cellular functions at the genetic level.

VI. PERSPECTIVES AND CLOSING REMARKS

Mechanotransduction has provided valuable insights into the biological mechanisms that drive aging and the potential for rejuvenation. This review has highlighted the intricate interplay between mechanical forces and cellular signaling pathways—not only in driving the aging process, but also in revealing novel therapeutic opportunities. By modulating mechanical environments and targeting key pathways such as Hippo/YAP, mTOR, and TGF-β/Smad, the burgeoning field of mechanomedicine aims to restore cellular homeostasis and tissue integrity. Emerging technologies, including mechanochemical therapies, nanoparticle systems, and ECM remodeling, have highlighted the therapeutic potential of integrating biomechanical strategies with aging interventions. These approaches offer promising avenues for mitigating age-related diseases, enhancing tissue regeneration, and extending lifespans.

Future research should prioritize the translation of mechanotransduction-based findings into clinical applications. Integrating machine learning with mechanobiological approaches can accelerate the identification of novel therapeutic targets, thereby enabling precision medicine for patients with age-related diseases. Multidisciplinary efforts combining biomechanics, regenerative medicine, and molecular biology are essential for developing targeted and noninvasive therapies. In addition, addressing challenges such as delivery mechanisms, treatment specificity, and long-term efficacy is critical for translating these therapies from the experimental stages to practical solutions. Mechanotransduction represents a paradigm shift in our understanding of aging and its treatment. By leveraging these intrinsic mechanical properties and pathways, we can decelerate the aging process and redefine the strategies used to enhance the quality of life of aging populations. Therefore, mechanomedicine is a promising frontier in the pursuit of healthier and more resilient societies.

ACKNOWLEDGMENTS

The authors thank the members of the Applied Mechanobiology Group (AMG) at Korea University for their constructive discussions on cellular mechanobiology. This study was supported by the KU-KIST Graduate School of Converging Science and Technology.

D.K. was supported by the National Research Foundation of Korea (NRF-2022M3H4A1A03067401, 2V10330-24-P039, RS-2023-00251315, RS-2023-00221182, and RS-2024-00507251) and the Ministry of Science and ICT (MSIT), South Korea, under the ICT Creative Consilience Program (IITP-2025-RS-2020-II201819) and supervised by the Institute of Information & Communications Technology Planning & Evaluation (IITP).

Note: This paper is part of the Special Topic on Mechanomedicine.

AUTHOR DECLARATIONS

Conflict of Interest

The authors have no conflicts to disclose.

Author Contributions

Hye-Min Han: Data curation (lead); Formal analysis (lead); Investigation (equal); Visualization (lead); Writing – original draft (lead); Writing – review & editing (lead). Su-Yeon Kim: Investigation (supporting); Visualization (supporting); Writing – original draft (supporting); Writing – review & editing (supporting). Dong-Hwee Kim: Conceptualization (lead); Funding acquisition (lead); Investigation (equal); Project administration (lead); Supervision (lead); Writing – original draft (supporting); Writing – review & editing (supporting).

DATA AVAILABILITY

The data that support the findings of this study are available within the article.

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Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Data Availability Statement

The data that support the findings of this study are available within the article.

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PERMALINK

Mechanotransduction for therapeutic approaches: Cellular aging and rejuvenation

Hye-Min Han

Su-Yeon Kim

Dong-Hwee Kim

Abstract

I. INTRODUCTION

II. THE BIOLOGY OF AGING: CELLULAR AND SYSTEMIC PERSPECTIVES

A. Aging at the systemic level

B. Causes of cellular senescence

C. Cellular aging and senescence

TABLE I.

III. BIOCHEMICAL PATHWAYS FOR AGING-ASSOCIATED MECHANOTRANSDUCTION

A. The TGF-β/Smad pathway

FIG. 1.

B. Wingless-related integration site (Wnt)/β-catenin pathway

C. mTOR pathway

D. The Janus kinase (JAK)/signal transducer and activator of transcription (STAT) pathway

E. The extracellular signal-regulated kinase (ERK) 1/2 pathway

F. The Hippo/YAP pathway

FIG. 2.

IV. MECHANOMEDICINE: DISEASE-SPECIFIC TARGETED THERAPY FOR CELLULAR REJUVENATION

A. Chronic inflammation

FIG. 3.

B. Cancer

C. Immune disorders

D. Other diseases

FIG. 4.

FIG. 5.

V. ENGINEERING APPLICATIONS OF MECHANOBIOLOGICAL THERAPIES

A. Mechanical modulation for cellular rejuvenation

B. Nanoparticles in mechanobiological therapies

FIG. 6.

C. Mechanochemical dynamic therapy (MDT)

FIG. 7.

VI. PERSPECTIVES AND CLOSING REMARKS

ACKNOWLEDGMENTS

AUTHOR DECLARATIONS

Conflict of Interest

Author Contributions

DATA AVAILABILITY

References

Associated Data

Data Availability Statement

ACTIONS

PERMALINK

RESOURCES

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