Reprogramming of adult cells to generate induced pluripotent stem cells (iPS cells) has opened new therapeutic opportunities; however, little is known about the possibility of in vivo reprogramming within tissues. Here we show that transitory induction of the four factors Oct4, Sox2, Klf4 and c-Myc in mice results in teratomas emerging from multiple organs, implying that full reprogramming can occur in vivo. Analyses of the stomach, intestine, pancreas and kidney reveal groups of dedifferentiated cells that express the pluripotency marker NANOG, indicative of in situ reprogramming.

Cancer is believed to arise primarily through accumulation of genetic mutations. Although induced pluripotent stem cell (iPSC) generation does not require changes in genomic sequence, iPSCs acquire unlimited growth potential, a characteristic shared with cancer cells. Here, we describe a murine system in which reprogramming factor expression in vivo can be controlled temporally with doxycycline (Dox). Notably, transient expression of reprogramming factors in vivo results in tumor development in various tissues consisting of undifferentiated dysplastic cells exhibiting global changes in DNA methylation patterns...

Reprogramming of differentiated cells into pluripotent cells can occur in vivo, but the mechanisms involved remain to be elucidated. Senescence is a cellular response to damage, characterized by abundant production of cytokines and other secreted factors that, together with the recruitment of inflammatory cells, result in tissue remodeling. Here, we show that in vivo expression of the reprogramming factors OCT4, SOX2, KLF4, and cMYC (OSKM) in mice leads to senescence and reprogramming, both coexisting in close proximity...

Ageing is a degenerative process that leads to tissue dysfunction and death. A proposed cause of ageing is the accumulation of epigenetic noise that disrupts gene expression patterns, leading to decreases in tissue function and regenerative capacity1,2,3. Changes to DNA methylation patterns over time form the basis of ageing clocks4, but whether older individuals retain the information needed to restore these patterns—and, if so, whether this could improve tissue function—is not known....

Aging is the major risk factor for many human diseases. In vitro studies have demonstrated that cellular reprogramming to pluripotency reverses cellular age, but alteration of the aging process through reprogramming has not been directly demonstrated in vivo. Here, we report that partial reprogramming by short-term cyclic expression of Oct4, Sox2, Klf4, and c-Myc (OSKM) ameliorates cellular and physiological hallmarks of aging and prolongs lifespan in a mouse model of premature aging. Similarly, expression of OSKM in vivo improves recovery from metabolic disease and muscle injury in older wild-type mice...

The expression of the pluripotency factors OCT4, SOX2, KLF4, and MYC (OSKM) can convert somatic differentiated cells into pluripotent stem cells in a process known as reprogramming. Notably, partial and reversible reprogramming does not change cell identity but can reverse markers of aging in cells, improve the capacity of aged mice to repair tissue injuries, and extend longevity in progeroid mice. However, little is known about the mechanisms involved. Here, we have studied changes in the DNA methylome, transcriptome, and metabolome in naturally aged mice subject to a single period of transient OSKM expression...

The ectopic expression of the transcription factors OCT4, SOX2, KLF4 and MYC (OSKM) enables reprogramming of differentiated cells into pluripotent embryonic stem cells. Methods based on partial and reversible in vivo reprogramming are a promising strategy for tissue regeneration and rejuvenation. However, little is known about the barriers that impair reprogramming in an in vivo context. We report that natural killer (NK) cells significantly limit reprogramming, both in vitro and in vivo...

The compromised ability of neurons to express Heat Shock Protein 70 (Hsp70) correlates with aging-related neurodegeneration. In this study, middle-aged and old mice were treated chronically until death with human Hsp70 delivered intranasally and were investigated after 5 or 9 mo of Hsp70 treatment for their cognitive ability and synaptic density. Hsp70 treatment extended mean and maximum lifespan, improved learning and memory in old animals, increased curiosity, decreased anxiety, and helped maintain synaptic structures that degrade with age...

MiR-455-3p TG mice lived 5 months longer than wild-type (WT) counterparts, whereas KO mice lived 4 months shorter than WT mice. Morris water maze test showed improved cognitive behavior, spatial learning and memory in miR-455-3p TG mice relative to age-matched WT mice and miR-455-3p KO mice. Further, mitochondrial biogenesis, dynamics and synaptic activities were enhanced in miR-455-3p TG mice, while these were reduced in KO mice. Overall, overexpressed miR-455-3p in mice displayed protective effects, whereas depleted miR-455-3p in mice exhibited deleterious effects in relation to lifespan, cognitive behavior, and mitochondrial and synaptic activities

Based on this notion, we tested the effects of a telomerase gene therapy in adult (1 year of age) and old (2 years of age) mice. Treatment of both groups of mice with an AAV of wide tropism expressing mouse telomerase (mTERT) demonstrated remarkable beneficial effects on health and fitness, improving several molecular biomarkers of aging. Moreover, telomerase‐treated mice did not develop more neoplasias comparing to their control littermates, suggesting that the known tumorigenic activity of telomerase is severely decreased when expressed in adult or old organisms...

Aging leads to a gradual decline in physical activity and disrupted energy homeostasis. The NAD⁺-dependent SIRT6 deacylase regulates aging and metabolism through mechanisms that largely remain unknown. Here, we show that SIRT6 overexpression leads to a reduction in frailty and lifespan extension in both male and female B6 mice. A combination of physiological assays, in vivo multi-omics analyses and ¹³C lactate tracing identified an age-dependent decline in glucose homeostasis and hepatic glucose output in wild type mice...

DNA repair has been hypothesized to be a longevity determinant, but the evidence for it is based largely on accelerated aging phenotypes of DNA repair mutants. Here, using a panel of 18 rodent species with diverse lifespans, we show that more robust DNA double-strand break (DSB) repair, but not nucleotide excision repair (NER), coevolves with longevity. Evolution of NER, unlike DSB, is shaped primarily by sunlight exposure. We further show that the capacity of the SIRT6 protein to promote DSB repair accounts for a major part of the variation in DSB repair efficacy between short- and long-lived species...

Mice overexpressing the mitotic checkpoint kinase gene BubR1 live longer, whereas mice hypomorphic for BubR1 (BubR1^H/H) live shorter and show signs of accelerated aging. As wild‐type mice age, BubR1 levels decline in many tissues, a process that is proposed to underlie normal aging and age‐related diseases. Understanding why BubR1 declines with age and how to slow this process is therefore of considerable interest. The sirtuins (SIRT1‐7) are a family of NAD⁺‐dependent deacetylases that can delay age‐related diseases....

Senescent cells, which accumulate in organisms over time, contribute to age-related tissue decline. Genetic ablation of senescent cells can ameliorate various age-related pathologies, including metabolic dysfunction and decreased physical fitness. While small-molecule drugs that eliminate senescent cells (‘senolytics’) partially replicate these phenotypes, they require continuous administration. We have developed a senolytic therapy based on chimeric antigen receptor (CAR) T cells targeting the senescence-associated protein urokinase plasminogen activator receptor (uPAR), and we previously showed these can safely eliminate senescent cells in young animals...

Cellular senescence is implicated as a contributing factor in the pathology of several age-related disorders and cancer development. Therefore, targeted removal of senescent cells has emerged as a promising treatment strategy for these conditions. However, current senolytic strategies that selectively eliminate senescent cells are limited by their toxicity and lack of potency. A recent study reported on the use of chimeric antigen receptor (CAR) T cell therapy as a novel senolytic approach and demonstrated improved cancer outcome and reversal of senescence-associated pathologies in animal models. Here, we aim to discuss the opportunities and limitations of translating such a therapeutic strategy into the clinic...

Cellular senescence contributes to aging and to aging-associated diseases, and depletion of senescent cells has shown potential for treating such diseases. Here, Yang et al. developed chimeric antigen receptor (CAR) T cells targeting Natural Killer Group 2 Member D (NKG2D) ligands, which are highly expressed on senescent cells. The CAR, which is comprised of the extracellular domain of NKG2D and the intracellular signaling domains of 4-1BB and CD3ζ, was able to efficiently drive killing of senescent cells in vitro and in vivo in both aged mice and aged nonhuman primates. Further, aged mice treated with NKG2D-CAR T cells exhibited improved physical performance after treatment. These data support further development of NKG2D-CAR T cells for aging-associated pathologies. —Courtney Malo

Cellular senescence represents a distinct cell fate characterized by replicative arrest in response to a host of extrinsic and intrinsic stresses. Senescence facilitates programming during development and wound healing, while limiting tumorigenesis. However, pathologic accumulation of senescent cells is implicated in a range of diseases and age-associated morbidities across organ systems. Senescent cells produce distinct paracrine and endocrine signals, causing local tissue dysfunction and exerting deleterious systemic effects...

Atherosclerosis is a disease of ageing, and the most common cause of death in the industrialized world. Cell senescence and the therapeutic removal of senescent cells using 'senolytics' are topical areas of science and translational medicine. A new study reports surprising findings on cell senescence and atherosclerosis with important therapeutic implications.

Cellular senescence is characterized by stable cell-cycle arrest and a secretory program that modulates the tissue microenvironment1,2. Physiologically, senescence serves as a tumour-suppressive mechanism that prevents the expansion of premalignant cells3,4 and has a beneficial role in wound-healing responses5,6. Pathologically, the aberrant accumulation of senescent cells generates an inflammatory milieu that leads to chronic tissue damage and contributes to diseases such as liver and lung fibrosis, atherosclerosis, diabetes and osteoarthritis1,7. Accordingly, eliminating senescent cells from damaged tissues in mice ameliorates the symptoms of these pathologies and even promotes longevity....

Cellular senescence is a cell state implicated in various physiological processes and a wide spectrum of age-related diseases. Recently, interest in therapeutically targeting senescence to improve healthy aging and age-related disease, otherwise known as senotherapy, has been growing rapidly. Thus, the accurate detection of senescent cells, especially in vivo, is essential. Here, we present a consensus from the International Cell Senescence Association (ICSA), defining and discussing key cellular and molecular features of senescence and offering recommendations on how to use them as biomarkers....

With age, senescent cells accumulate in the skin and spread the aging phenotype to neighboring cells, resulting in decreased thickness, regenerative capacity, and a barrier effect in the skin.Aging and cellular senescence phenotypes in the skin were found to correlate with immunosenescence, longevity, or cardiovascular disease risk.Skin aging, induced by ultraviolet radiation, has an impact in the brain, by decreasing hippocampal neurogenesis and activating the central hypothalamic–pituitary–adrenal axis.Senolytics, such as dasatinib and fisetin, are drugs that selectively eliminate senescent cells and are already topically administered to the skin, showing potential antiaging effects.

During this last decade, the development of prosenescence therapies has become an attractive strategy as cellular senescence acts as a barrier against tumour progression. In this context, CDK4/6 inhibitors induce senescence and reduce tumour growth in breast cancer patients. However, even though cancer cells are arrested after CDK4/6 inhibitor treatment, genes regulating senescence in this context are still unknown limiting their antitumour activity. Here, using a functional genome-wide CRISPR/Cas9 genetic screen we found several genes that participate in the proliferation arrest induced by CDK4/6 inhibitors...

Senescence is a cellular phenotype present inhealth and disease, characterized by a stablecell-cycle arrest and an inflammatory responsecalled senescence-associated secretory phenotype(SASP). The SASP is important in influencing thebehavior of neighboring cells and altering the microenvironment; yet, this role has been mainly attributed to soluble factors. Here, we show that boththe soluble factors and small extracellular vesicles(sEVs) are capable of transmitting paracrine senescence to nearby cells. Analysis of individual cellsinternalizing sEVs, using a Cre-reporter system,show a positive correlation between sEV uptakeand senescence activation. We find an increase inthe number of multivesicular bodies during senescence in vivo. sEV protein characterization bymass spectrometry (MS) followed by a functionalsiRNA screen identify interferon-induced transmembrane protein 3 (IFITM3) as being partially responsible for transmitting senescence to normal cells.We find that sEVs contribute to paracrine senescence

The effect of immunometabolism on age-associated diseases remains uncertain. In this work, we show that T cells with dysfunctional mitochondria owing to mitochondrial transcription factor A (TFAM) deficiency act as accelerators of senescence. In mice, these cells instigate multiple aging-related features, including metabolic, cognitive, physical, and cardiovascular alterations, which together result in premature death. T cell metabolic failure induces the accumulation of circulating cytokines, which resembles the chronic inflammation that is characteristic of aging (“inflammaging”)....

Whether and how certain transposable elements with viral origins, such as endogenous retroviruses (ERVs) dormant in our genomes, can become awakened and contribute to the aging process is largely unknown. In human senescent cells, we found that HERVK (HML-2), the most recently integrated human ERVs, are unlocked to transcribe viral genes and produce retrovirus-like particles (RVLPs). These HERVK RVLPs constitute a transmissible message to elicit senescence phenotypes in young cells, which can be blocked by neutralizing antibodies. The activation of ERVs was also observed in organs of aged primates and mice as well as in human tissues and serum from the elderly. Their repression alleviates cellular senescence and tissue degeneration and, to some extent, organismal aging. These findings indicate that the resurrection of ERVs is a hallmark and driving force of cellular senescence and tissue aging.