TITLE: “Heterochronic parabiosis for the study of the effects of aging on stem cells and their niches”
SOURCE: Conboy IM, Rando TA. Heterochronic parabiosis for the study of the effects of aging on stem cells and their niches. Cell Cycle. 2012 Jun 15;11(12):2260-7.
SUMMARY: Aging is unmistakable and undeniable in mammals. Interestingly, mice develop cataracts, muscle atrophy, osteoporosis, obesity, diabetes and cognitive deficits after just 2-3 postnatal years, while it takes seven or more decades for the same age-specific phenotypes to develop in humans. Thus, chronological age corresponds differently with biological age in metazoan species and although many theories exist, we do not understand what controls the rate of mammalian aging. One interesting idea is that species-specific rate of aging represents a ratio of tissue attrition to tissue regeneration. Furthermore, current findings suggest that the age-imposed biochemical changes in the niches of tissue stem cells inhibit performance of this regenerative pool, which leads to the decline of tissue maintenance and repair. If true, slowing down stem cell and niche aging, thereby promoting tissue regeneration, could slow down the process of tissue and organismal aging. In this regard, recent studies of heterochronic parabiosis provide important clues as to the mechanisms of stem cell aging and suggest novel strategies for enhancing tissue repair in the old. Here we review current literature on the relationship between the vigor of tissue stem cells and the process of aging, with an emphasis on the rejuvenation of old tissues by the extrinsic modifications of stem cell niches.
PUBLIC DOWNLOAD OF FULL MANUSCRIPT: Conboy 2012 PDF
TITLE: “Heterochronic parabiosis: historical perspective and methodological considerations for studies of aging and longevity”
SOURCE: Conboy MJ, Conboy IM, Rando TA. Heterochronic parabiosis: historical perspective and methodological considerations for studies of aging and longevity. Aging Cell. 2013 Jun;12(3):525-30.
SUMMARY: Pairing two animals in parabiosis to test for systemic or circulatory factors from one animal affecting the other animal has been used in scientific studies for at least 150 years. These studies have led to advances in fields as diverse as endocrinology, immunology, and oncology. A variation on the technique, heterochronic parabiosis, whereby two animals of different ages are joined to test for systemic regulators of aspects of aging or age-related diseases also has almost a century-long scientific history. In this review, we focus on the history of heterochronic parabiosis, methodological considerations and caveats, and the major advances that have emerged from those studies, including recent advances in our understanding of stem cell aging.
PUBLIC DOWNLOAD OF FULL MANUSCRIPT: Conboy 2013 PDF
TITLE: “Delayed animal aging through the recovery of stem cell senescence by platelet rich plasma”
SOURCE: Liu HY, Huang CF, Lin TC, Tsai CY, Tina Chen SY, Liu A, Chen WH, Wei HJ, Wang MF, Williams DF, Deng WP. Delayed animal aging through the recovery of stem cell senescence by platelet rich plasma. Biomaterials. 2014 Dec;35(37):9767-9776.
SUMMARY: Aging is related to loss of functional stem cell accompanying loss of tissue and organ regeneration potentials. Previously, we demonstrated that the life span of ovariectomy-senescence accelerated mice (OVX-SAMP8) was significantly prolonged and similar to that of the congenic senescence-resistant strain of mice after platelet rich plasma (PRP)/embryonic fibroblast transplantation. The aim of this study is to investigate the potential of PRP for recovering cellular potential from senescence and then delaying animal aging. We first examined whether stem cells would be senescent in aged mice compared to young mice. Primary adipose derived stem cells (ADSCs) and bone marrow derived stem cells (BMSCs) were harvested from young and aged mice, and found that cell senescence was strongly correlated to animal aging. Subsequently, we demonstrated that PRP could recover cell potential from senescence, such as promote cell growth (cell proliferation and colony formation), increase osteogenesis, decrease adipogenesis, restore cell senescence related markers and resist the oxidative stress in stem cells from aged mice. The results also showed that PRP treatment in aged mice could delay mice aging as indicated by survival, body weight and aging phenotypes (behavior and gross morphology) in term of recovering the cellular potential of their stem cells compared to the results on aged control mice. In conclusion these findings showed that PRP has potential to delay aging through the recovery of stem cell senescence and could be used as an alternative medicine for tissue regeneration and future rejuvenation.
PUBLIC DOWNLOAD OF FULL MANUSCRIPT: Not publicly available
TITLE: “Transplantation of mesenchymal stem cells from young donors delays aging in mice”
SOURCE: Shen J, Tsai YT, Dimarco NM, Long MA, Sun X, Tang L. Transplantation of mesenchymal stem cells from young donors delays aging in mice. Sci Rep. 2011;1:67.
SUMMARY: Increasing evidence suggests that the loss of functional stem cells may be important in the aging process. Our experiments were originally aimed at testing the idea that, in the specific case of age-related osteoporosis, declining function of osteogenic precursor cells might be at least partially responsible. To test this, aging female mice were transplanted with mesenchymal stem cells from aged or young male donors. We find that transplantation of young mesenchymal stem cells significantly slows the loss of bone density and, surprisingly, prolongs the life span of old mice. These observations lend further support to the idea that age-related diminution of stem cell number or function may play a critical role in age-related loss of bone density in aging animals and may be one determinant of overall longevity.
PUBLIC DOWNLOAD OF FULL MANUSCRIPT: Shen 2011 PDF
TITLE: “Aged mice repeatedly injected with plasma from young mice: a survival study”
SOURCE: Shytikov D, Balva O, Debonneuil E, Glukhovskiy P, Pishel I. Aged mice repeatedly injected with plasma from young mice: a survival study. Biores Open Access. 2014 Oct 1;3(5):226-32.
SUMMARY: It was reported using various biological models that the administration of blood factors from young animals to old animals could rejuvenate certain functions. To assess the anti-aging effect of young blood we tested the influence of repeated injections of plasma from young mice on the lifespan of aged mice. One group of 36 CBA/Ca female mice aged 10-12 months was treated by repeated injections of plasma from 2- to 4-month-old females (averaging 75-150 μL per injection, once intravenously and once intraperitoneally per week for 16 months). Their lifespan was compared to a control group that received saline injections. The median lifespan of mice from the control group was 27 months versus 26.4 months in plasma-treated group; the repeated injections of young plasma did not significantly impact either median or maximal lifespan.
PUBLIC DOWNLOAD OF FULL MANUSCRIPT: Shytikov 2014 PDF
TITLE: “Young blood reverses age-related impairments in cognitive function and synaptic plasticity in mice”
SOURCE: Villeda SA, Plambeck KE, Middeldorp J, Castellano JM, Mosher KI, Luo J, Smith LK, Bieri G, Lin K, Berdnik D, Wabl R, Udeochu J, Wheatley EG, Zou B, Simmons DA, Xie XS, Longo FM, Wyss-Coray T. Young blood reverses age-related impairments in cognitive function and synaptic plasticity in mice. Nat Med. 2014 Jun;20(6):659-63.
SUMMARY: As human lifespan increases, a greater fraction of the population is suffering from age-related cognitive impairments, making it important to elucidate a means to combat the effects of aging. Here we report that exposure of an aged animal to young blood can counteract and reverse pre-existing effects of brain aging at the molecular, structural, functional and cognitive level. Genome-wide microarray analysis of heterochronic parabionts–in which circulatory systems of young and aged animals are connected–identified synaptic plasticity-related transcriptional changes in the hippocampus of aged mice. Dendritic spine density of mature neurons increased and synaptic plasticity improved in the hippocampus of aged heterochronic parabionts. At the cognitive level, systemic administration of young blood plasma into aged mice improved age-related cognitive impairments in both contextual fear conditioning and spatial learning and memory. Structural and cognitive enhancements elicited by exposure to young blood are mediated, in part, by activation of the cyclic AMP response element binding protein (Creb) in the aged hippocampus. Our data indicate that exposure of aged mice to young blood late in life is capable of rejuvenating synaptic plasticity and improving cognitive function.
PUBLIC DOWNLOAD OF FULL MANUSCRIPT: Villeda 2014 PDF
TITLE: “Concise review: hematopoietic stem cell aging and the prospects for rejuvenation”
SOURCE: Wahlestedt M, Pronk CJ, Bryder D. Concise review: hematopoietic stem cell aging and the prospects for rejuvenation. Stem Cells Transl Med. 2015 Feb;4(2):186-94.
SUMMARY: Because of the continuous increases in lifetime expectancy, the incidence of age-related diseases will, unless counteracted, represent an increasing problem at both the individual and socioeconomic levels. Studies on the processes of blood cell formation have revealed several shortcomings as a consequence of chronological age. They include a reduced ability to mount adaptive immune responses and a blood cell composition skewed toward myeloid cells, with the latter coinciding with a dramatically increased incidence of myelogenous diseases, including cancer. Conversely, the dominant forms of acute leukemia affecting children associate with the lymphoid lineages. A growing body of evidence has suggested that aging of various organs and cellular systems, including the hematopoietic system, associates with a functional demise of tissue-resident stem cell populations. Mechanistically, DNA damage and/or altered transcriptional landscapes appear to be major drivers of the hematopoietic stem cell aging state, with recent data proposing that stem cell aging phenotypes are characterized by at least some degree of reversibility. These findings suggest the possibility of rejuvenating, or at least dampening, stem cell aging phenotypes in the elderly for therapeutic benefit.
PUBLIC DOWNLOAD OF FULL MANUSCRIPT: Wahlestedt 2015 PDF
TITLE: “Preclinical Assessment of Young Blood Plasma for Alzheimer Disease”
SOURCE: Middeldorp J, Lehallier B, Villeda SA, Miedema SS, Evans E, Czirr E, Zhang H, Luo J, Stan T, Mosher KI, Masliah E, Wyss-Coray T. Preclinical Assessment of Young Blood Plasma for Alzheimer Disease. JAMA Neurol. 2016 Nov 1;73(11):1325-1333.
SUMMARY: Alzheimer disease (AD) pathology starts long before clinical symptoms manifest, and there is no therapy to treat, delay, or prevent the disease. A shared blood circulation between 2 mice (aka parabiosis) or repeated injections of young blood plasma (plasma from 2- to 3-month-old mice) into old mice has revealed benefits of young plasma on synaptic function and behavior. However, to our knowledge, the potential benefit of young blood has not been tested in preclinical models of neurodegeneration or AD. To determine whether young blood plasma ameliorates pathology and cognition in a mouse model for AD and could be a possible future treatment for the disease. In this preclinical study, mice that harbor a human mutant APP gene, which causes familial AD, were aged to develop AD-like disease including accumulation of amyloid plaques, loss of synaptic and neuronal proteins, and behavioral deficits. The initial parabiosis studies were done in 2010, and the final studies were conducted in 2014. Alzheimer disease model mice were then treated either by surgically connecting them with a young healthy mouse, thus providing a shared blood circulation through parabiosis, or through repeated injections of plasma from young mice. Neuropathological parameters and changes in hippocampal gene expression in response to the treatment were assessed. In addition, cognition was tested in AD model mice intravenously injected with young blood plasma. Aged mutant amyloid precursor protein mice with established disease showed a near complete restoration in levels of synaptic and neuronal proteins after exposure to young blood in parabiosis (synaptophysin P = .02; calbindin P = .02) or following intravenous plasma administration (synaptophysin P < .001; calbindin P = .14). Amyloid plaques were not affected, but the beneficial effects in neurons in the hippocampus were accompanied by a reversal of abnormal extracellular receptor kinase signaling (P = .05), a kinase implicated in AD. Moreover, young plasma administration was associated with improved working memory (P = .01) and associative memory (P = .02) in amyloid precursor protein mice. Factors in young blood have the potential to ameliorate disease in a model of AD. PUBLIC DOWNLOAD OF FULL MANUSCRIPT: Middeldorp 2016 PDF
TITLE: “Intercellular Transfer of Microvesicles from Young Mesenchymal Stromal Cells Rejuvenates Aged Murine Hematopoietic Stem Cells”
SOURCE: Kulkarni R, Bajaj M, Ghode S, Jalnapurkar S, Limaye L, Kale VP. Intercellular Transfer of Microvesicles from Young Mesenchymal Stromal Cells Rejuvenates Aged Murine Hematopoietic Stem Cells. Stem Cells. 2018 Mar;36(3):420-433.
SUMMARY: Donor age is one of the major concerns in bone marrow transplantation, as the aged hematopoietic stem cells (HSCs) fail to engraft efficiently. Here, using murine system, we show that a brief interaction of aged HSCs with young mesenchymal stromal cells (MSCs) rejuvenates them and restores their functionality via inter-cellular transfer of microvesicles (MVs) containing autophagy-related mRNAs. Importantly, we show that MSCs gain activated AKT signaling as a function of aging. Activated AKT reduces the levels of autophagy-related mRNAs in their MVs, and partitions miR-17 and miR-34a into their exosomes, which upon transfer into HSCs downregulate their autophagy-inducing mRNAs. Our data identify previously unknown mechanisms operative in the niche-mediated aging of HSCs. Inhibition of AKT in aged MSCs increases the levels of autophagy-related mRNAs in their MVs and reduces the levels of miR-17 and miR-34a in their exosomes. Interestingly, transplantation experiments showed that the rejuvenating power of these “rescued” MVs is even better than that of the young MVs. We demonstrate that such ex vivo rejuvenation of aged HSCs could expand donor cohort and improve transplantation efficacy.
PUBLIC DOWNLOAD OF FULL MANUSCRIPT: Kulkarni 2018 PDF
TITLE: “Extracellular vesicles extracted from young donor serum attenuate inflammaging via partially rejuvenating aged T-cell immunotolerance”
SOURCE: Wang W, Wang L, Ruan L, Oh J, Dong X, Zhuge Q, Su DM. Extracellular vesicles extracted from young donor serum attenuate inflammaging via partially rejuvenating aged T-cell immunotolerance. FASEB J. 2018 May 21:fj201800059R.
SUMMARY: Biologic aging results in a chronic inflammatory condition, termed inflammaging, which establishes a risk for such age-related diseases as neurocardiovascular diseases; therefore, it is of great importance to develop rejuvenation strategies that are able to attenuate inflammaging as a means of intervention for age-related diseases. A promising rejuvenation factor that is present in young blood has been found that can make aged neurons younger; however, the component in the young blood and its mechanism of action are poorly elucidated. We assessed rejuvenation in naturally aged mice with extracellular vesicles (EVs) or exosomes extracted from young murine serum on the basis of different spectrums of microRNAs in these vesicles from young and old sera. We found that EVs extracted from young donor mouse serum, rather than EVs extracted from old donor mouse serum or non-EV supernatant extracted from young donor mouse serum, were able to attenuate inflammaging in old mice. Inflammaging is attributed to multiple factors, one of which is thymic aging-released self-reactive T cell-induced pathology. We found that the attenuation of inflammaging after treatment with EVs from young serum partially contributed to the rejuvenation of thymic aging, which is characterized by partially reversed thymic involution, enhancement of negative selection signals, and reduced autoreactions in the periphery. Our results provide evidence for understanding of the potential rejuvenation factor in the young donor serum, which holds great promise for the development of novel therapeutics to reduce morbidity and mortality caused by age-related inflammatory diseases.
PUBLIC DOWNLOAD OF FULL MANUSCRIPT: Not publicly available
TITLE: “Young bone marrow transplantation preserves learning and memory in old mice”
SOURCE: Das MM, Godoy M, Chen S, Moser VA, Avalos P, Roxas KM, Dang I, Yáñez A, Zhang W, Bresee C, Arditi M, Liu GY, Svendsen CN, Goodridge HS. Young bone marrow transplantation preserves learning and memory in old mice. Commun Biol. 2019 Feb 20;2:73.
SUMMARY: Restoration of cognitive function in old mice by transfer of blood or plasma from young mice has been attributed to reduced C-C motif chemokine ligand 11 (CCL11) and β2-microglobulin, which are thought to suppress neurogenesis in the aging brain. However, the specific role of the hematopoietic system in this rejuvenation has not been defined and the importance of neurogenesis in old mice is unclear. Here we report that transplantation of young bone marrow to rejuvenate the hematopoietic system preserved cognitive function in old recipient mice, despite irradiation-induced suppression of neurogenesis, and without reducing β2-microglobulin. Instead, young bone marrow transplantation preserved synaptic connections and reduced microglial activation in the hippocampus. Circulating CCL11 levels were lower in young bone marrow recipients, and CCL11 administration in young mice had the opposite effect, reducing synapses and increasing microglial activation. In conclusion, young blood or bone marrow may represent a future therapeutic strategy for neurodegenerative disease.
PUBLIC DOWNLOAD OF FULL MANUSCRIPT: Das 2019 PDF