Selective removal of senescent cells, or senolytic therapy, has been proposed to be a potent strategy for overcoming age-related diseases and even for reversing aging. We found that nintedanib, a tyrosine kinase inhibitor, selectively induced the death of primary human dermal fibroblasts undergoing replicative senescence. Similar to ABT263, a well-known senolytic agent, nintedanib triggered intrinsic apoptosis in senescent cells. Additionally, at the concentration producing the senolytic effect, nintedanib arrested the cell cycle of nonsenescent cells in the G1 phase without inducing cytotoxicity.

Interestingly, the mechanism by which nintedanib activated caspase-9 in the intrinsic apoptotic pathway differed from that of ABT263 apoptosis induction; specifically, nintedanib did not decrease the levels of Bcl-2 family proteins in senescent cells. Moreover, nintedanib suppressed the activation of the JAK2/STAT3 pathway, which caused the drug-induced death of senescent cells. STAT3 knockdown in senescent cells induced caspase activation. Moreover, nintedanib reduced the number of senescence-associated β-galactosidase-positive senescent cells in parallel with a reduction in STAT3 phosphorylation and ameliorated collagen deposition in a mouse model of bleomycin-induced lung fibrosis. Consistently, nintedanib exhibited a senolytic effect through bleomycin-induced senescence of human pulmonary fibroblasts.

Overall, we found that nintedanib can be used as a new senolytic agent and that inhibiting STAT3 may be an approach for inducing the selective death of senescent cells. Our findings pave the way for expanding the senolytic toolkit for use in various aging statuses and age-related diseases.

The dedifferentiation of somatic cells into a pluripotent state by cellular reprogramming coincides with a reversal of age-associated molecular hallmarks. Although transcription factor induced cellular reprogramming has been shown to ameliorate these aging phenotypes in human cells and extend health and lifespan in mice, translational applications of this approach are still limited. More recently, chemical reprogramming via small molecule cocktails have demonstrated a similar ability to induce pluripotency in vitro, however, its potential impact on aging is unknown.

Here, we demonstrated that partial chemical reprogramming is able to improve key drivers of aging including genomic instability and epigenetic alterations in aged human cells. Moreover, we identified an optimized combination of two reprogramming molecules sufficient to induce the amelioration of additional aging phenotypes including cellular senescence and oxidative stress. Importantly, in vivo application of this two-chemical combination significantly extended C. elegans lifespan by 42%. Together, these data demonstrate that improvement of key drivers of aging and lifespan extension is possible via chemical induced partial reprogramming, opening a path towards future translational applications.

As the cell's recycling system, lysosomes contain potent digestive enzymes that degrade molecular waste. These contents are walled off from damaging other parts of the cell with a membrane that acts like a chain link fence around a hazardous waste facility. Although breaks can occur in this fence, a healthy cell quickly repairs the damage. An enzyme called PI4K2A accumulated on damaged lysosomes within minutes and generated high levels of a signaling molecule called PtdIns4P, which recruits other molecules called ORPs. ORP proteins work like tethers. One end of the protein binds to the PtdIns4P red flag on the lysosome, and the other end binds to the endoplasmic reticulum, the cellular structure involved in synthesis of proteins and lipids.

The endoplasmic reticulum wraps around the lysosome like a blanket. Normally, the endoplasmic reticulum and lysosomes barely touch each other, but once the lysosome was damaged, researchers found that they were embracing. Through this embrace, cholesterol and a lipid called phosphatidylserine are shuttled to the lysosome and help patch up holes in the membrane fence. Phosphatidylserine also activates a protein called ATG2, which acts like a bridge to transfer other lipids to the lysosome, the final membrane repair step in the newly described PITT - or phosphoinositide-initiated membrane tethering and lipid transport - pathway.

The researchers suspect that in healthy people, small breaks in the lysosome membrane are quickly repaired through the PITT pathway. But if the damage is too extensive or the repair pathway is compromised - due to age or disease - leaky lysosomes accumulate. In Alzheimer's, leakage of tau fibrils from damaged lysosomes is a key step in progression of the disease.

Lysosomal dysfunction has been increasingly linked to disease and normal ageing. Lysosomal membrane permeabilization (LMP), a hallmark of lysosome-related diseases, can be triggered by diverse cellular stressors. Given the damaging contents of lysosomes, LMP must be rapidly resolved, although the underlying mechanisms are poorly understood. Here, using an unbiased proteomic approach, we show that LMP stimulates a phosphoinositide-initiated membrane tethering and lipid transport (PITT) pathway for rapid lysosomal repair.

Upon LMP, phosphatidylinositol-4 kinase type 2α (PI4K2A) accumulates rapidly on damaged lysosomes, generating high levels of the lipid messenger phosphatidylinositol-4-phosphate. Lysosomal phosphatidylinositol-4-phosphate in turn recruits multiple oxysterol-binding protein (OSBP)-related protein (ORP) family members, including ORP9, ORP10, ORP11, and OSBP, to orchestrate extensive new membrane contact sites between damaged lysosomes and the endoplasmic reticulum. The ORPs subsequently catalyse robust endoplasmic reticulum-to-lysosome transfer of phosphatidylserine and cholesterol to support rapid lysosomal repair.

Finally, the lipid transfer protein ATG2 is also recruited to damaged lysosomes where its activity is potently stimulated by phosphatidylserine. Independent of macroautophagy, ATG2 mediates rapid membrane repair through direct lysosomal lipid transfer. Together, our findings identify that the PITT pathway maintains lysosomal membrane integrity, with important implications for numerous age-related diseases characterized by impaired lysosomal function.

The common view is that T lymphocytes activate telomerase to delay senescence. Here we show that some T cells (primarily naïve and central memory cells) elongated telomeres by acquiring telomere vesicles from antigen-presenting cells (APCs) independently of telomerase action. Upon contact with these T cells, APCs degraded shelterin to donate telomeres, which were cleaved by the telomere trimming factor TZAP, and then transferred in extracellular vesicles at the immunological synapse.

Telomere vesicles retained the Rad51 recombination factor that enabled telomere fusion with T-cell chromosome ends lengthening them by an average of ~3,000 base pairs. Thus, there are antigen-specific populations of T cells whose ageing fate decisions are based on telomere vesicle transfer upon initial contact with APCs. These telomere-acquiring T cells are protected from senescence before clonal division begins, conferring long-lasting immune protection.

How senescent T cells are formed remains poorly understood. We propose a model whereby telomere transfer from APCs protects the recipient T cells from replicative senescence. The recipient is preferably a naïve or central memory T cell. When recipient T cells acquire telomeres from APCs during antigen presentation, they shift towards a stem-like/central long-lived memory state. Failure to acquire telomeres skews them towards senescence instead.

It is not clear how T cells with APC telomeres will divide upon telomere transfer; however, these T cells may subsequently divide and differentiate both linearly and/or asymmetrically after antigen stimulation, if telomere transfer occurs. It is possible that antigen strength may affect the amount of telomere transfer and subsequent division of T cells. However, even in situations where antigen specificity was identical, a large proportion of T cells still failed to acquire telomeres from APCs, shifting towards a short-lived effector state; some of these cells may serve as senescent progenitors. Therefore, additional mechanisms that control telomere transfer during the process of antigen, presentation beyond T-cell receptor specificity, would have to exist.

We suggest that senescent T cells, or their progenitors, may be short-lived cells that are continuously generated by episodes of activation that lack telomere transfer. An important but as-yet-undefined function of the immunological synapse is, therefore, immediate determination of senescence fates of T cells. The intercellular telomere transfer reaction we described is a different form of decentralized immunity whereby APCs distribute telomeres to favour some T cells becoming long-lived memory cells, bypassing senescence. Decentralization indicates that T cells do not rely on just a single molecule, telomerase, to extend telomeres. Whether the memory T cells generated in the absence of telomere transfer have the same longevity outlook than those telomere-acquiring T cells we have studied remains to be determined.

We posit that Alzheimer's disease (AD) is driven by amyloid-β (Aβ) generated in the amyloid-β protein precursor (AβPP) independent pathway, which is activated by AβPP-derived Aβ accumulated intraneuronally, in a life-long process. This interpretation constitutes the Amyloid Cascade Hypothesis 2.0 (ACH2.0). It defines a tandem intraneuronal-Aβ (iAβ)-anchored cascade occurrence: intraneuronally-accumulated, AβPP-derived iAβ triggers relatively benign cascade that activates the AβPP-independent iAβ-generating pathway, which, in turn, initiates the second, devastating cascade that includes tau pathology and leads to neuronal loss.

The entire output of the AβPP-independent iAβ-generating pathway is retained intraneuronally and perpetuates the pathway's operation. This process constitutes a self-propagating, autonomous engine that drives AD and ultimately kills its host cells. Once activated, the AD Engine is self-reliant and independent from Aβ production in the AβPP proteolytic pathway; operation of the former renders the latter irrelevant to the progression of AD by relegating its iAβ contribution to insignificance, and making its manipulation for therapeutic purposes, such as via BACE (beta-site AβPP-cleaving enzyme) inhibition, as futile.

In the proposed AD paradigm, the only valid direct therapeutic strategy is targeting the engine's components, and the most effective feasible approach appears to be the activation of BACE1 and/or of its homolog BACE2, with the aim of exploiting their Aβ-cleaving activities. Such treatment would collapse the iAβ population and 'reset' its levels below those required for the operation of the AD Engine. Any sufficiently selective iAβ-depleting treatment would be equally effective. Remarkably, this approach opens the possibility of a short-duration, once-in-a-lifetime-only or very infrequent, preventive or curative therapy for AD; this therapy would be also effective for prevention and treatment of the 'common' pervasive aging-associated cognitive decline.

The ACH2.0 clarifies all ACH-unresolved inconsistencies, explains the widespread 'resilience to AD' phenomenon, predicts occurrences of a category of AD-afflicted individuals without excessive Aβ plaque load and of a novel type of familial insusceptibility to AD; it also predicts the lifespan-dependent inevitability of AD in humans if untreated preventively. The article details strategy and methodology to generate an adequate AD model and validate the hypothesis; the proposed AD model may also serve as a research and drug development platform.

β2-microglobulin (β2M) is a small protein that is expressed in all nucleated cells, previous data showed that its activity increases during inflammation. β2M interplays with cytokines for instance, IL-6, IL-8 and others intracellularly to induce inflammatory responses. In addition, it can bind and modulate the activity of growth factors and hormones and receptors. β2M has been exploited as a biomarker for many disorders with inflammatory components.

Our group previously showed that β2M expressed highly in senescent cells, and recently it has been shown by our group that β2M expressed highly in blood samples of old people comparing to youngers. Furthermore, we have shown that β2M correlated significantly with oxidative stress biomarkers, which could underscore a potential role in oxidative stress network. Therefore, there is a rationality to test the expression of β2M across different group of age using other easier source of sample such as buccal cells.

Buccal cells are epithelial cells that are similar to brain and skin in nature. Buccal cells can be collected easily, deriving a high number of cells that can be used for different biological assays. Comparing to other sample methods, buccal cell samples are less invasive and very easy to collect. In addition, buccal cells are very stable after isolation from the mouth, which makes them easy to process and analyze. Moreover, buccal cells are easy to preserve, making them an easy source for diagnosis.

In this study, we used buccal cells to examine the expression of β2M in different age groups. The expression of β2M increased significantly with fold change 3.40, 4.80, 6.60, 8.20 and 12.04 for the group of age 18-25 years, 26-35 years, 36-45 years, 46-55 years, and 56-70 years respectively. The same observation was seen with markers of biological aging (p16INK4a) with fold change 3.19, 3.90, 4.80, 8.50 and 12.40 for the group of age 18-25 years, 26-35 years, 36-45 years, 46-55 years, and 56-70 years respectively.

As expected, there was an increase in expression of inflammatory genes (IL-1β and IL-6) in the elderly. Moreover, there was a direct significant correlation (Pearson correlation coefficient, r = 90) between β2M expression and age, and the same direct significant correlation between p16INK4a expression and age was also seen (r = 90). In addition, a direct correlation between β2M and p16INK4a was also seen (r = 0.83), there was also direct correlation between β2M and IL-1β (r = 0.5) and IL-6 (r = 0.68).

This evidence showed that β2M increased in buccal cells of the elderly compared to younger, and thereby buccal cells can be exploited to assess biological aging by measuring β2M levels, however, large sample size and using another assessing method such as β2M protein levels should be performed to confirm the results.

Aging is a primary risk factor for cognitive dysfunction and exacerbates multiple biological processes in the brain, including but not limited to nutrient sensing dysregulation, insulin sensing dysfunction and histone deacetylation. Therefore, pharmaceutical intervention of aging targeting several distinct but overlapping pathways provides a basis for testing combinations of drugs as a cocktail. A recent study showed that middle-aged mice treated with a drug cocktail of rapamycin, acarbose, and phenylbutyrate for three months had increased resilience to age related cognitive decline. This finding provided the rationale to investigate the comprehensive transcriptomic and molecular changes within the brain of mice that received this cocktail treatment or control substance.

Transcriptome profiles were generated through RNA sequencing and pathway analysis was performed by gene set enrichment analysis to evaluate the overall RNA message effect of the drug cocktail. Molecular endpoints representing aging pathways were measured through immunohistochemistry to further validate the attenuation of brain aging in the hippocampus of mice that received the cocktail treatment, each individual drug or controls. Results indicated that biological processes that enhance aging were suppressed, while autophagy was increased in the brains of mice given the drug cocktail. The molecular endpoint assessments indicated that treatment with the drug cocktail was overall more effective than any of the individual drugs for relieving cognitive impairment by targeting multiple aging pathways.

Physical exercise is thought to have beneficial effects on the symptoms of Parkinson's disease (PD). Irisin is an exercise-induced myokine released into the circulation. We therefore tested whether irisin itself could have a beneficial effect on pathologic α-synuclein (α-syn) accumulation and concomitant neurodegeneration in PD.

Here, we show that irisin prevents pathologic α-synuclein (α-syn)-induced neurodegeneration in the α-syn preformed fibril (PFF) mouse model of sporadic PD. Intravenous delivery of irisin via viral vectors following the injection of α-syn PFF cause a reduction in the formation of pathologic α-syn and prevented the loss of dopamine neurons and lowering of striatal dopamine. Irisin also substantially reduced the α-syn PFF-induced motor deficits as assessed behaviorally by the pole and grip strength test.

In vitro, recombinant sustained irisin treatment of primary cortical neurons attenuated α-syn PFF toxicity by reducing the formation of phosphorylated serine 129 of α-syn and neuronal cell death. Tandem mass spectrometry and biochemical analysis revealed that irisin reduced pathologic α-syn by enhancing endolysosomal degradation of pathologic α-syn. Our findings highlight the potential for therapeutic disease modification of irisin in PD.

"Proteins in the blood are under constant and changing pressure because of the different ways blood flows throughout the body. For example, blood flows more slowly through small blood vessels in the eyes compared to larger arteries around the heart. Blood proteins need to be able to respond to these changes, and this study gives us fundamental truths about how they adapt to their environment, which is critical to targeting those proteins for future treatments."

There are hundreds of proteins in our blood, but the researchers focused on vitronectin, one of the most abundant. In addition to circulating in high concentrations in the blood, vitronectin is found in the scaffolding between cells and is also an important component of cholesterol. "This protein is an important target for macular degeneration because it accumulates in the back of the eye, causing vision loss. Similar deposits appear in the brain in Alzheimer's disease and in the arteries in atherosclerosis. We want to understand why this happens and leverage this knowledge to develop new treatments."

To approach this question, the researchers were interested in learning how the protein changes its structure at different temperatures and under different levels of pressure, approximating what happens in the human body. Through detailed biochemical analysis, the researchers found that the protein can subtly change its shape under pressure. These changes cause it to bond more easily to calcium ions in the blood, which the researchers suggest leads to the buildup of calcified plaque deposits characteristic of macular degeneration and other age-related diseases. "It's a very subtle rearrangement of the molecular structure, but it has a big impact on how the protein functions. The more we learn about the protein on a structural and mechanistic level, the better chance we have of successfully targeting it with treatments."

Step-based recommendations may be appropriate for dementia-prevention guidelines. However, the association of step count and intensity with dementia incidence is unknown. This study examined the dose-response association between daily step count and intensity and incidence of all-cause dementia among adults in the UK. This was a UK Biobank prospective population-based cohort study (February 2013 to December 2015) with 6.9 years of follow-up (data analysis conducted May 2022). A total of 78,430 of 103,684 eligible adults aged 40 to 79 years with valid wrist accelerometer data were included. Registry-based dementia was ascertained through October 2021.

We found no minimal threshold for the beneficial association of step counts with incident dementia. Our findings suggest that approximately 9,800 steps per day may be optimal to lower the risk of dementia. We estimated the minimum dose at approximately 3,800 steps per day, which was associated with 25% lower incident dementia. This finding suggests that population-wide dementia prevention might be improved by shifting away from the least-active end of the step-count distributions. Unlike previous studies investigating mortality outcomes, our analyses highlight the importance of stepping intensity for preventing dementia. Both purposeful steps and peak 30-minute cadence (i.e. an indicator of overall best natural effort in a free-living environment) were associated with lower risks of dementia.

The risk of chronic diseases caused by aging is reduced by caloric restriction (CR)-induced immunometabolic adaptation. Here, we found that the matricellular protein, secreted protein acidic and rich in cysteine (SPARC), was inhibited by 2 years of 14% sustained CR in humans and elevated by obesity. SPARC converted anti-inflammatory macrophages into a pro-inflammatory phenotype with induction of interferon-stimulated gene (ISG) expression via the transcription factors IRF3/7.

Mechanistically, SPARC-induced ISGs were dependent on toll-like receptor-4 (TLR4)-mediated TBK1, IRF3, IFN-β, and STAT1 signaling without engaging the Myd88 pathway. Metabolically, SPARC dampened mitochondrial respiration, and inhibition of glycolysis abrogated ISG induction by SPARC in macrophages. Furthermore, the N-terminal acidic domain of SPARC was required for ISG induction, while adipocyte-specific deletion of SPARC reduced inflammation and extended health span during aging. Collectively, SPARC, a CR-mimetic adipokine, is an immunometabolic checkpoint of inflammation and interferon response that may be targeted to delay age-related metabolic and functional decline.

Fibrosis is the final path of nearly every form of chronic disease, regardless of the pathogenesis. Upon chronic injury, activated, fibrogenic fibroblasts deposit excess extracellular matrix, and severe tissue fibrosis can occur in virtually any organ. However, antifibrotic therapies that target fibrogenic cells, while sparing homeostatic fibroblasts in healthy tissues, are limited. We tested whether specific immunization against endogenous proteins, strongly expressed in fibrogenic cells but highly restricted in quiescent fibroblasts, can elicit an antigen-specific cytotoxic T cell response to ameliorate organ fibrosis.

In silico epitope prediction revealed that activation of the genes Adam12 and Gli1 in profibrotic cells and the resulting "self-peptides" can be exploited for T cell vaccines to ablate fibrogenic cells. We demonstrate the efficacy of a vaccination approach to mount CD8+ T cell responses that reduce fibroblasts and fibrosis in the liver and lungs in mice. These results provide proof of principle for vaccination-based immunotherapies to treat fibrosis.

Age is the main risk factor for neurodegenerative disorders with dementia and movement dysfunction including Alzheimer's Disease (AD), Dementia with Lewy bodies (DLB), and Parkinson's Disease (PD). While in AD, amyloid beta (Aβ) and tau play a central role, in DLB and PD, ɑ-synuclein (ɑ-syn) is a key mediator. However, ɑ-syn has been shown to accumulate in the brain during aging and in AD and in DLB, Aβ, and tau are also found in conjunction with ɑ-syn in selected brain regions.

Under physiological conditions ɑ-syn is an intracellular protein that might play a role in neuroplasticity, however during aging and under pathological conditions ɑ-syn aggregates can be released to the extracellular space leading to cell to cell propagation spreading and seeding of small aggregates into preformed protofibrils (pff) and fibrils in neighboring neuronal and non-neuronal cells. Recent evidence has shown that the intrinsic structure of ɑ-syn fibrils dictates the characteristic of the synucleinopathies and for instance inoculation of selected ɑ-syn pff into the CNS can reproduce several aspects of the pathology of DLB/PD in wild type animals models.

Although protein aggregation and spreading have been extensively studied, less is known about the contribution of aging. One possibility by which aging might lead to neurodegeneration is dysregulation in immune cell function. This might be in part mediated by extracellular ɑ-syn propagating to glial cells. For example, it has been shown that ɑ-syn can activate innate immune responses via Toll like receptors.

In this study we evaluated the role of aging in neurodegeneration in the ɑ-syn pff model. We found that inoculation of ɑ-syn pff in aged mice resulted in greater spreading and deficits compared to young mice, with ɑ-syn pff-inducing gene networks in young mice that overlapped with genes differentially expressed in aged mice. We propose that changes in inflammatory gene expression underly the increased susceptibility of aged mice to enhanced ɑ-syn induced pathology and might represent a new avenue for therapeutics.

Aging has attracted curiosity and elicited imagination throughout human history. However, it has been only 30 years since a new epoch in aging research was established after the isolation of the first long-lived strains in C. elegans. Nowadays, studies in the aging field are exploding with the ever-expanding knowledge of the molecular and cellular bases of life and diseases, whilst subjected to scientific scrutiny. In this current review, we summarize the cutting-edge developments in aging research, presenting the landscape of aging across multiple layers.

In the first chapter, at the cellular level, we focus on cellular senescence, a main culprit of aging, harnessing a panel of phenotypes from various aspects to reveal underlying molecular alterations and mechanisms. In addition, cellular senescence bridges aging and cancer, for which aging is a major risk factor but the causal relationship still remains elusive. On one hand, cellular senescence constitutes a potent, cell autonomous anti-cancer mechanism in vivo of higher eukaryotes; on the other hand, cellular senescence accumulating with age may evoke intrinsic reprogramming of stem cells and contribute to tumor-promoting microenvironment through SASP and inflammaging.

Amongst all cell types, stem cell aging is of particular interest, as their exhaustion and dysfunction impair tissue function and regeneration capacity and lead to age-associated disorders, driving impacts way up to organismal aging. Indeed, aging is manifested as a multisystemic deterioration throughout the body that leads to declining tissue and organ functions. What we have learned about cellular aging from the first chapter are also reflected at the tissue level; and moreover, in this aging community of cells, they are affected by each other in the same tissue through the microenvironment, or even across tissues by systemic factors.

In the second chapter, we summarize aging-associated changes that occur in various tissues and organs, including those in the circulatory system, hematopoietic and immune system, nervous system, musculoskeletal system, reproductive system, digestive system as well as the microbiota therein. Collectively, understanding mechanisms and identifying targets of tissue/organ aging open vistas to therapeutic interventions for alleviating aging and age-associated disorders.

Finally, in the third chapter, we review geroprotective approaches in the hope to rewind the biological clock to a youthful state. This can be achieved by targeting key pro-/reverse-aging factors to rejuvenate aged cells, by eliminating senescent cells, or by transplanting genetically-modified stem cells. The rejuvenating effect can be local or systematic. Sophisticated strategies have been developed to deliver it through gene therapy, antibodies, or small molecule-based drugs.

We are now entering an inspiring era of aging research. According to new scientific findings summarized here and in other equivalent publications, this era now offers unprecedented hope for extending human healthspan: preventing, delaying or, even in certain cases, reversing many of the signs of aging. Whether this era promises to extend the longest human lifespan still remains an open question. However, what is clear is that after 30 years of fundamental research linking specific genes to aging, although many aspects still await further investigation, such as the interplay between metabolism and systemic aging, a solid foundation has been established, and clinical trials for interventions that target the aging process are being initiated. Although we may encounter considerable difficulties in applying this research to humans, the potential rewards in healthy aging far outweigh the risks.

Fibroblasts are mesenchymal cells that account for the majority of the cellular density of the dermis and have a crucial role in wound healing. Until recently, fibroblasts were not considered to have extensive involvement in the field of scarless wound healing and were seen only as extracellular matrix (ECM) producing cells. It is now understood that there are many lineages of human fibroblasts with distinct and heterogeneous functions. Simply, some of these fibroblasts lead to scarring and some lead to regeneration. The early human foetus has mainly regenerative fibroblasts, but during aging the number of scarring fibroblasts increase to become the majority in the adult.

Scarring is the typical physiological outcome of wound healing. It is an evolutionary adaptation that provides quick and effective repair to damaged tissues, sometimes at the expense of tissue integrity and function. Scar tissue lacks skin appendages and has an organised collagen structure replacing the typical "basket-weave" dermal structure in unwounded tissues, leading to reduced tensile strength. Ideal wound repair would involve regeneration of the normal skin structure, including its associated appendages.

The ability to prevent scarring has applications beyond cosmetic and aesthetic uses, with the ability to restore function to extensively damaged tissues and preclude pathological scarring. This article describes current understanding of fibroblast heterogenicity and involvement in wound healing, focusing on the role of fibroblasts during physiological scarring. We also present the current most promising targets involving fibroblasts in the reduction of scarring and how we can manipulate the behaviour of fibroblasts to mimic the wound regeneration models in the human foetus. These targets include the pro-fibrotic EN1 positive fibroblast lineage, TGFβ1 inhibition, and genetic therapies utilising miRNAs and siRNAs.