Anti-aging Strategies Research Articles

Effects of Target of Rapamycin and Phosphatidylinositol 3-Kinase Inhibitors and Other Autophagy-Related Supplements on Life Span in y w Male Drosophila melanogaster

Various dietary supplements have been shown to extend the life span of Drosophila melanogaster, including several that promote autophagy, such as rapamycin and spermidine. The goal of the study presented here was to test numerous additional potential anti-aging supplements, primarily inhibitors of the target of rapamycin (TOR) and/or phosphatidylinositol 3-kinase (PI3K). Using a single, comparatively long-lived y w test strain, screening was performed in male flies supplemented either throughout adulthood or, in a few cases, beginning in middle or late adult life, with concentrations spanning 4–6 orders of magnitude in most cases. Supplementation with PP242 and deferiprone, an iron chelator, beginning in late adult life had no positive effect on life span. Lifelong supplementation with Ku-0063794, LY294002, PX-866-17OH, Torin2 and WYE-28 had no effect at any dose. Rapamycin, spermidine and wortmannin all had significant life-shortening effects at the highest doses tested. AZD8055, PI-103 hydrochloride and WYE-132 yielded slight beneficial effects at 1–2 doses, but only 100 nM AZD8055 was confirmed to have a minor (1.3%) effect in a replicate experiment, which was encompassed by other control groups within the same study. These compounds had no effect on fly fecundity (egg laying) or fertility (development of progeny to adulthood), but equivalent high doses of rapamycin abolished fertility. The solvent DMSO had no significant effect on life span at the concentrations used to solubilize most compounds in the fly medium, but it drastically curtailed both survival and fertility at higher concentrations. 2-Hydroxypropyl-β-cyclodextrin also failed to extend the life span when provided throughout adulthood or beginning in mid-adult life. Collectively, the results suggest that inhibition of the TOR/PI3K pathway and autophagy through dietary intervention is not a straightforward anti-aging strategy in Drosophila and that further extension of life is difficult in comparatively long-lived flies.

Spermidine protects cellular redox status and ionic homeostasis in D-galactose induced senescence and natural aging rat models.

Impaired redox homeostasis is an important hallmark of aging. Among various anti-aging interventions, caloric restriction mimetics (CRMs) are the most effective inpromoting health and longevity. The potential role of spermidine (SPD) as a CRM in modulating oxidative stress and redox homeostasis during aging remains unclear. Thisstudy aimed to investigate the protective effect of SPD inD-galactose (D-gal) accelerated induced senescence model and naturally aged rats. Young male rats (4months), D-gal induced (500 mg/kg b. w., subcutaneously) aging model and naturally aged (22months) rats were supplemented with SPD (10 mg/kg b. w., orally) for 6weeks. The results showed that SPD supplementation suppresses the age induced increase in reactive oxygen species, lipid peroxidation andprotein oxidation. Additionally, it increases the level ofantioxidants, plasma membrane redox system in erythrocytes and membrane. These results also indicate that membrane transporter activity is correlated with the susceptibility of the erythrocyte towards oxidative damage. We therefore present evidence that SPD improves redox status and membrane impairments in erythrocytes in experimental and naturally aging rat models, however, more research is required to recommend a potential therapeutic role for SPD as an anti-aging intervention strategy.

Antiaging in a Bottle: Bioactive Competency of Plasma-Generated Nitric Oxide Water for Modulation of Aging-Related Signature in Human Dermal Cells.

Nitric oxide (NO), a potential therapeutic antiaging molecule, modulates various physiological and cellular processes. However, alterations in endogenous NO levels brought on by aging impact multiple organ systems and heighten susceptibility to age-related skin diseases. This correlation underscores the importance of investigating NO-based antiaging interventions. Nonthermal plasma-generated NO is a promising avenue for cosmetic and regenerative medicine due to its capacity to stimulate cellular growth. Herein, we examine the potential of plasma-generated nitric oxide water (NOW) as a bioactive agent in human dermal fibroblasts, emphasizing gene expression patterns linked to extracellular matrix (ECM) breakdown and cellular senescence. The findings of our study indicate that administering NOW at lower dosages enhances cell migration and proliferation. Moreover, the genetic signatures associated with ECM synthesis, antioxidant defense, and antisenescence pathways have been analyzed in NOW-exposed cells. Notably, the downregulation of ECM-degrading enzyme transcripts─collagenase, elastase, and hyaluronidase─suggests NOW's potential in mitigating the intrinsic skin aging phenomena, emphasizing the promise of NO-based interventions in advancing antiaging strategies within regenerative medicine.

Cellular Senescence and Anti-Aging Strategies in Aesthetic Medicine: A Bibliometric Analysis and Brief Review.

Skin aging is the most obvious feature of human aging, and delaying aging has become a hot and difficult research topic in aesthetic medicine. The accumulation of dysfunctional senescent cells is one of the important mechanisms of skin aging, based on which a series of anti-aging strategies have been generated. In this paper, from the perspective of cellular senescence, we utilize bibliometrics and research review to explore the research hotspots and trends in this field, with a view to providing references for skin health and aesthetic medicine. We obtained literature related to this field from the Web of Science Core Collection database from 1994 to 2024. Bibliometrix packages in R, CiteSpace, VOSviewer, Origin, and Scimago Graphica were utilized for data mining and visualization. A total of 2,796 documents were included in the analysis. The overall trend of publications showed a continuous and rapid increase from 2016-2023, but the total citations improved poorly over time. In this field, Journal of Cosmetic Dermatology, Journal of Investigative Dermatology, Experimental Gerontology are core journals. Kim J, Lee JH, Lee S, Rattan SIS, Chung JH and Kim JH are the core authors in this field. Seoul National University is the first in terms of publications. Korea is the country with the most publications, but USA has the most total citations. Top 10 keywords include: gene-expression, skin, cellular senescence, cell, oxidative stress, antioxidants, in vitro, fibroblasts, mechanism, cancer. Current research trends are focused on neurodegeneration, skin rejuvenation, molecular docking, fibrosis, wound healing, SASP, skin barrier, and antioxidants. The core literature and references reflect topics such as the major molecular pathways in the aging process, and the relationship with tumors. This field of research has been rapidly rising in recent years. Relevant research hotspots focus on oxidative stress, fibroblasts, and senescence-associated secretory phenotype. Anti-aging strategies targeting cellular senescence hold great promise, including removal of senescent cells or attenuation of SASP factors, corresponding to senolytics and senomorphics therapies, respectively.

Sirtuin 3 reinforces acylcarnitine metabolism and maintains thermogenesis in brown adipose tissue of aging mice.

Acylcarnitine (ACar) is a novel fuel source for activating thermogenesis in brown adipose tissue (BAT). However, whether ACar metabolism underlies BAT thermogenesis decline with aging remain unclear. Here, the L-carnitine-treated young and aging mice were used to investigate the effects of activation of ACar metabolism on BAT thermogenesis during aging. We showed that long term L-carnitine feeding, which results in an elevation in circulating ACar levels, failed to improve cold sensitivity of aging mice, which still displayed impaired thermogenesis and ACar metabolism in interscapular BAT (iBAT). The RNA-sequencing was used to identify the key regulator for the response of aging mice to LCar induced activation of ACar metabolism in BAT, and we identified Sirt3 as a key regulator for the response of aging mice to L-carnitine induced activation of ACar metabolism in iBAT. Then the adipose-specific Sirt3 knockout (Sirt3 AKO) mice were used to investigate the role of Sirt3 in ACar metabolism and thermogenesis of BAT and explore the underlying mechanism, and the results showed that Sirt3 AKO mice displayed defective ACar metabolism and thermogenesis in iBAT. Mechanically, Sirt3 regulated ACar metabolism via HIF1α-PPARα signaling pathway to promote iBAT thermogenesis, and knockdown or inhibition of HIF1α ameliorated impaired ACar metabolism and thermogenesis of iBAT in the absence of Sirt3. Collectively, we propose that Sirt3 regulated ACar metabolism is critical in maintaining thermogenesis in BAT of aging mice, which can promote the development of anti-aging intervention strategy.

Enhancing skin aging parameter assessment in clinical trials: AI-Driven analysis of ultrasound images

BackgroundHigh-frequency ultrasound (HFUS) imaging offers valuable insights into skin aging parameters in clinical trials. However, manual measurements are time-consuming and operator-dependent, necessitating the exploration of automated approaches. ObjectiveThis study aimed to develop, train, and validate an artificial intelligence model for automated HFUS image parameter acquisition in dermatological assessments. A secondary goal was its application in evaluating data from an anti-aging skin therapy clinical trial. MethodsSupervised machine learning algorithms were used to predict target variables from ultrasound images. The best models were selected through independent validation. A training dataset of 144 ultrasound skin images and a validation set of 40 images were employed. A clinical trial involved 34 female subjects with aging skin signs, randomized into two groups: (1) cosmetic formulation plus therapeutic unfocused ultrasound (TUS) and (2) placebo formulation plus TUS. HFUS imaging was conducted before and after a 4-week and 8-week study period. ResultsOur algorithms successfully predicted echogenicity and thickness variables, showing competitive performance. In the clinical trial, the treatment group exhibited a significant improvement in skin echogenicity, while no significant changes were observed in the placebo group. ConclusionThis study demonstrates the feasibility of automating the prediction of bioimage variables for anti-aging strategy development. Mathematical algorithms reduced HFUS image evaluations to minutes, expediting clinical trial progress.

Bulk RNA Barcode Sequencing Reveals Role of RNA Splicing in Aging Dermal Stem Cell Modulation by a Botanical Extract

Skin aging is a complex, multifaceted process influenced by both intrinsic and extrinsic factors. Understanding the molecular mechanisms underlying skin aging is crucial for developing effective anti-aging strategies. Dermal stem cells play a pivotal role in maintaining skin homeostasis, but their functionality is compromised with aging. This study investigated the impact of aging on dermal stem cells and explored the potential of natural extracts in modulating their biological characteristics. Using bulk RNA barcoding and sequencing (BRB-seq), we identified differentially expressed genes (DEGs) between young and aged dermal stem cells, revealing alterations in cellular processes, including cell proliferation, ECM synthesis, and RNA splicing. We also demonstrated that a natural extract, comprising callus cells and Alpine rose leaf extracts, influenced RNA splicing in aged dermal stem cells, leading to improved dermal structure and integrity in vitro. Our findings suggest that natural extracts may exert their effects through senolytic activity and the modulation of RNA splicing, a process crucial to gene expression and cellular function. This study underscores the potential of integrating high-throughput transcriptomics in understanding skin aging, presenting new avenues for the development of innovative, sustainable, and effective anti-aging strategies.

Tauroursodeoxycholic acid targets HSP90 to promote protein homeostasis and extends healthy lifespan.

As the elderly population expands, the pursuit of therapeutics to reduce morbidity and extend lifespan has become increasingly crucial. As an FDA-approved drug for chronic cholestatic liver diseases, tauroursodeoxycholic acid (TUDCA), a natural bile acid, offers additional health benefits beyond liver protection. Here, we show that TUDCA extends the lifespan and healthspan of C. elegans. Importantly, oral supplementation of TUDCA improves fitness in old mice, including clinically relevant phenotypes, exercise capacity and cognitive function. Consistently, TUDCA treatment drives broad transcriptional changes correlated with anti-aging characteristics. Mechanistically, we discover that TUDCA targets the chaperone HSP90 to promote its protein refolding activity. This collaboration further alleviates aging-induced endoplasmic reticulum (ER) stress and facilitates protein homeostasis, thus offering resistance to aging. In summary, our findings uncover new molecular links between an endogenous metabolite and protein homeostasis, and propose a novel anti-aging strategy that could improve both lifespan and healthspan.

Proteomic Mendelian randomization to identify protein biomarkers of telomere length

Shortening of telomere length (TL) is correlated with many age-related disorders and is a hallmark of biological aging. This study used proteome-wide Mendelian randomization to identify the protein biomarkers associated with telomere length. Protein quantitative trait loci (pQTL) were derived from two studies, the deCODE Health study (4907 plasma proteins) and the UK Biobank Pharma Proteomics Project (2923 plasma proteins). Summary data from genome-wide association studies (GWAS) for TL were obtained from the UK Biobank (472,174 cases) and GWAS Catalog (418,401 cases). The association between proteins and TL was further assessed using colocalization and summary data-based Mendelian randomization (SMR) analyses. The protein–protein network, druggability assessment, and phenome-wide MR were used to further evaluate the potential biological effects, druggability, and safety of the target proteins. Proteome-wide MR analysis identified 22 plasma proteins that were causally associated with telomere length. Five of these proteins (APOE, SPRED2, MAX, RALY, and PSMB1) had the highest evidence of association with TL and should be prioritized. This study revealed telomere length-related protein biomarkers, providing new insights into the development of new treatment targets for chronic diseases and anti-aging intervention strategies.

The effect of degeneration of elastic fibres on loss of elasticity and wrinkle formation.

Skin elasticity, which is vital for a youthful appearance, depends on the elastic fibres in the dermis. However, these fibres deteriorate with ageing, resulting in wrinkles and sagging. Changes that occur in the elastic fibres in living human skin and the relationship between elastic fibres and the state of the skin surface remain unclear. Therefore, it is necessary to verify the relationship between elastic fibres and skin elasticity. In this study, we investigated the association of the elastic fibre structure with skin elasticity and stratum corneum protein content in living human skin. Thirty-five female volunteers aged 25-66 years were included in this study. Elastic fibres were observed using a multiphoton scanning laser biomicroscope. Skin elasticity was measured using a Cutometer, and stratum corneum proteins (Heat-shock protein 27 [HSP27] and galectin-7 [Gal-7]) in tape-stripped samples were analysed using an enzyme-linked immunosorbent assay. Elastic fibres exhibited increased curvature and thickness with increased age, with fragmentation observed in women aged >60 years. Elastin scores, which reflect thinness and curvature, were negatively correlated with age, whereas they were positively correlated with R7 elasticity (recovery ability). In individuals aged 20-30 years, higher levels of inflammatory markers (HSP27 and Gal-7) correlated with lower elastin scores; however, this trend was not observed in older participants. Elastic fibre deterioration worsened after 40 years of age, and this effect correlated with reduced skin recovery and increased wrinkles. In younger individuals, inflammatory markers affected elastic fibres. These findings can guide anti-ageing strategies that focus on elastic fibre preservation and inflammation control.

Adipose tissue senescence: Biological changes, hallmarks and therapeutic approaches

Adipose tissue (AT), the largest energy storage reservoir and endocrine organ, plays a crucial role in regulating systemic energy metabolism. As one of the most vulnerable tissues during aging, the plasticity of AT is impaired. With age, AT undergoes redistribution, characterized by expansion of visceral adipose tissue (VAT) and reduction of peripheral subcutaneous adipose tissue (SAT). Additionally, age-related changes in AT include reduced adipogenesis of white adipocytes, decreased proliferation and differentiation capacity of mesenchymal stromal/stem cells (MSCs), diminished thermogenic capacity in brown/beige adipocytes, and dysregulation of immune cells. Specific and sensitive hallmarks enable the monitoring and evaluation of the biological changes associated with aging. In this study, we have innovatively proposed seven characteristic hallmarks of AT senescence, including telomere attrition, epigenetic alterations, genomic instability, mitochondrial dysfunction, disabled macroautophagy, cellular senescence, and chronic inflammation, which are intricately interconnected and mutually regulated. Finally, we discussed anti-aging strategies targeting AT, offering insights into mitigating or delaying metabolic disturbances caused by AT senescence.

The Reproductive Lifespan of Ovarian Follicle.

The functional unit within mammalian ovaries is the ovarian follicle. The development of the ovarian follicle is a lengthy process beginning from the time of embryogenesis, passing through multiple different stages of maturation. The purpose of this review is to describe the most basic events in the journey of ovarian follicle development, discussing the importance of ovarian reserve and highlighting the role of several factors that affect oocyte quality and quantity during aging including hormonal, genetic and epigenetic factors. Novel, promising anti-aging strategies are also discussed.

Integrating Machine Learning with Multi-Omics Technologies in Geroscience: Towards Personalized Medicine.

Aging is a fundamental biological process characterized by a progressive decline in physiological functions and an increased susceptibility to diseases. Understanding aging at the molecular level is crucial for developing interventions that could delay or reverse its effects. This review explores the integration of machine learning (ML) with multi-omics technologies-including genomics, transcriptomics, epigenomics, proteomics, and metabolomics-in studying the molecular hallmarks of aging to develop personalized medicine interventions. These hallmarks include genomic instability, telomere attrition, epigenetic alterations, loss of proteostasis, disabled macroautophagy, deregulated nutrient sensing, mitochondrial dysfunction, cellular senescence, stem cell exhaustion, altered intercellular communication, chronic inflammation, and dysbiosis. Using ML to analyze big and complex datasets helps uncover detailed molecular interactions and pathways that play a role in aging. The advances of ML can facilitate the discovery of biomarkers and therapeutic targets, offering insights into personalized anti-aging strategies. With these developments, the future points toward a better understanding of the aging process, aiming ultimately to promote healthy aging and extend life expectancy.

Anti-ageing interventions for the treatment of cardiovascular disease.

As the global demographic landscape continues to shift towards an aged population, so does the medical and socioeconomic burden of cardiovascular diseases. Indeed, ageing is one of, if not the, key risk factor for the development of cardiovascular diseases. However, there are currently no approved cardiovascular therapeutics that primarily target the molecular and cellular mechanisms underlying the ageing process itself. In this review, we present the potential of emerging anti-ageing strategies, including epigenetic rejuvenation, metabolic reprogramming, autophagy activation, as well as senolytic and anti-inflammatory therapies, in delaying or reversing the development of age-related cardiovascular disorders, while considering potential sex differences. In doing so, we implicate cellular ageing processes in the pathogenesis of several prevalent cardiovascular diseases, such as atherosclerosis, hypertension, various types of cardiomyopathies (including its hypertrophic, ischemic, dilated, diabetic, and arrhythmogenic forms) and heart failure, particularly that with preserved ejection fraction. Finally, we outline future challenges and steps needed for the implementation of these novel anti-ageing strategies in the clinical setting, with the aim of challenging the long-held notion of ageing as a 'nonmodifiable' risk factor for cardiovascular diseases.

An estimate of the longitudinal pace of aging from a single brain scan predicts dementia conversion, morbidity, and mortality.

To understand how aging affects functional decline and increases disease risk, it is necessary to develop accurate and reliable measures of how fast a person is aging. Epigenetic clocks measure aging but require DNA methylation data, which many studies lack. Using data from the Dunedin Study, we introduce an accurate and reliable measure for the rate of longitudinal aging derived from cross-sectional brain MRI: the Dunedin Pace of Aging Calculated from NeuroImaging or DunedinPACNI. Exporting this measure to the Alzheimer's Disease Neuroimaging Initiative and UK Biobank neuroimaging datasets revealed that faster DunedinPACNI predicted participants' cognitive impairment, accelerated brain atrophy, and conversion to diagnosed dementia. Underscoring close links between longitudinal aging of the body and brain, faster DunedinPACNI also predicted physical frailty, poor health, future chronic diseases, and mortality in older adults. Furthermore, DunedinPACNI followed the expected socioeconomic health gradient. When compared to brain age gap, an existing MRI aging biomarker, DunedinPACNI was similarly or more strongly related to clinical outcomes. DunedinPACNI is a "next generation" MRI measure that will be made publicly available to the research community to help accelerate aging research and evaluate the effectiveness of dementia prevention and anti-aging strategies.

The influential responsibility of sirtuins in senescence and associated diseases: A review.

Aging is a process of time-associated depletion in the physiological functions, essential for the survival and reproducibility of living beings. Some age-related disorders can be successfully controlled with some biomedical techniques or pharmaceutical approaches. There are some precise remedies that demonstrate conspicuous promise in the preclinical and clinical setup of extending lifespan or enhancing health by altering natural senescence. The sirtuin family of proteins is one of the most favorable targets for antiaging strategies. Sirtuins were initially identified as transcription repressors in yeast, but today they are known to exist in bacteria and eukaryotes, as well as humans. The SIRT (1-7) family of proteins in humans is made up of seven members, each of which has either mono-ADP ribosyl transferase or deacetylase activity. Researchers suggest that sirtuins are essential for cell metabolism and play a major role in how cells react to various stimuli, such as oxidative or genotoxic stress. A healthy lifestyle, which includes exercise and a balanced diet, has been demonstrated to impact health span by adjusting the levels of sirtuins, suggesting the involvement of sirtuins in extending human longevity. The hunt for sirtuin activators is among the most extensive and comprehensive research subjects in the present scenario. Some optimism has been generated to investigate antiaging therapies by natural compounds, such as curcumin and others. This review article highlights the role of sirtuins in native senescence and their primordial roles in the progression of several life-threatening diseases. Further, it also provides recent information on the sirtuin activators and inhibitors and their therapeutic benefits.

Unveiling the causal relationship between circulating levels of micronutrients and risk of facial aging: A Mendelian randomization study.

Facial aging involves a continuous sequence of complex, interrelated events that impact numerous facial tissues. The aim of the study was to elucidate the casual relationship between circulating micronutrients and risk of facial aging. A two-sample Mendelian randomization analysis was performed using genetic data from genome-wide association studies. The inverse-variance weighted method is used for causal effect estimation, and additional tools such as Mendelian randomization-Egger, weighted median, simple mode, and weighted mode were used to refine the analysis. We conducted an in-depth examination of the correlation between several micronutrient blood levels and the risk of facial aging, and identified 3 key micronutrients (selenium, carotene, and iron) that may have a significant impact on skin health. Inverse-variance weighted results indicate that selenium levels were positively correlated with the risk of facial aging (odds ratio [OR] 1.005, P = .027), while a negative causal effect of carotene (OR 0.979, P = .024) and iron (OR 0.976, P = .009) on age-related facial alterations was observed. This study offers a new and insightful perspective on the current understanding of antiaging strategies, particularly the importance of appropriate consumption of essential micronutrients to maintain healthy skin condition.

Effects of light exposure on human ultra-weak photon emission: Preliminary findings for a pioneering control tool in cosmetics

Currently, the cosmetic industry is developing several treatments based on the use of lights with different wavelengths for anti-ageing strategies and facial rejuvenation. Some lights have been proven to be beneficial for our skincare, but their actual effects require an in-depth analysis.Ultra-weak photon emission (UPE) is a spontaneous, low intensity emission from all living systems produced as a consequence of metabolic reactions (e.g., oxidative metabolism, cell division, photosynthesis, or carcinogenesis). However, it can also be induced by several factors, such as light exposure, wounds, thermal shock, and other stress elements. Thus, measuring human biophotonic emission can open new horizons to explore the real benefits of light therapies, particularly regarding the direct relationship between light exposure and free radicals, such as reactive oxygen species (ROS), which are the main cause of UPE.In this study, the ultra-weak photon emission from a sample of ten human beings after exposure to different lights was studied using red and green lights (artificially produced by an RGB LED lamp) and natural light (directly received from the sun), aiming to assess the UPE changes when directly focusing these types of lights on the skin. Hence, this technique could be proposed as a pioneering control tool in cosmetics, principally with phototherapies.Our preliminary results showed that the UPE response after light stimulation differed when a person was exposed to artificial lights compared to sunlight. Besides, there were relevant variations between women and men that should be deeply examined in further investigations by increasing the number of participating subjects in this experience. Furthermore, it was serendipitously discovered that the presence of certain unusual elements in our body, such as using hyaluronic acid fillers and having white hair (natural or dyed), could change the UPE intensity of our skin.

Skin Aging and the Upcoming Role of Ferroptosis in Geroscience.

The skin is considered the most important organ system in mammals, and as the population ages, it is important to consider skin aging and anti-aging therapeutic strategies. Exposure of the skin to various insults induces significant changes throughout our lives, differentiating the skin of a young adult from that of an older adult. These changes are caused by a combination of intrinsic and extrinsic aging. We report the interactions between skin aging and its metabolism, showing that the network is due to several factors. For example, iron is an important nutrient for humans, but its level increases with aging, inducing deleterious effects on cellular functions. Recently, it was discovered that ferroptosis, or iron-dependent cell death, is linked to aging and skin diseases. The pursuit of new molecular targets for ferroptosis has recently attracted attention. Prevention of ferroptosis is an effective therapeutic strategy for the treatment of diseases, especially in old age. However, the pathological and biological mechanisms underlying ferroptosis are still not fully understood, especially in skin diseases such as melanoma and autoimmune diseases. Only a few basic studies on regulated cell death exist, and the challenge is to turn the studies into clinical applications.

Functional hyaluronic acid microneedles for skin photoaging based on collagen induction and oxidative stress regulation strategies

Photoaging holds remarkable importance for skin health and senescence. Ultraviolet (UV) irradiation results in the disruption of the extracellular matrix (ECM) microenvironment, the degradation of collagen, and the generation of oxidative stress. Traditional hyaluronic acid (HA) exhibits a diminished capacity to stimulate collagen regeneration, and hampered by its poor permeability as a macromolecule, ultimately resulting in constrained therapeutic outcomes for the treatment of photoaging. In this study, HA/PX was prepared by functional modification of HA with sulfonate-rich or phosphatidylcholine-rich polymers, which could complement the loss of ECM and ameliorate the senescence of human fibroblasts (HDFs) and hairless mouse models subjected to UVB-induced photoaging. The results indicate that HA/PX exhibits superior abilities in delaying cellular aging, promoting collagen regeneration, and resisting reactive oxygen species (ROS) compared to HA. Furthermore, HA/PX shows good biocompatibility both in vivo and in vitro, without causing allergic reactions or other adverse effects. We also demonstrated that the transdermal delivery of HA/PX via microneedle arrays (MNs) can significantly mitigate wrinkles and skin damage in photoaged nude mice, and achieve the treatment of skin photoaging by enhancing epidermal thickness, promoting collagen deposition, and reducing oxidative stress. Therefore, our research offers a novel possibility for future anti-aging therapeutic strategies.