Transient non-integrative expression of nuclear reprogramming factors promotes multifaceted amelioration of aging in human cells

Sarkar, Tapash Jay; Quarta, Marco; Mukherjee, S; Colville, Alex; Paine, Patrick; Doan, Linda; Tran, Chanh; Chu, Constance R.; Horvath, Steve; Qi, Lei S.; Bhutani, Nidhi; Rando, Thomas A.; Sebastiano, Vittorio

doi:10.1038/s41467-020-15174-3

Cited by 202 publications

(187 citation statements)

References 41 publications

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“…Additional tissues' samples were used for work on other ideas and hypothesis (in progress). Of note, recent studies, comparable in scope and methods, published in high impact journals, have N =3-4 with even when the ES is lower, and Variance is larger than that of current work [12].…”

Section: Introductionmentioning

confidence: 77%

Rejuvenation of three germ layers tissues by exchanging old blood plasma with saline-albumin

Mehdipour

Skinner

Wong

et al. 2020

Aging

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Heterochronic blood sharing rejuvenates old tissues, and most of the studies on how this works focus on young plasma, its fractions, and a few youthful systemic candidates. However, it was not formally established that young blood is necessary for this multi-tissue rejuvenation. Here, using our recently developed small animal blood exchange process, we replaced half of the plasma in mice with saline containing 5% albumin (terming it a "neutral" age blood exchange, NBE) thus diluting the plasma factors and replenishing the albumin that would be diminished if only saline was used. Our data demonstrate that a single NBE suffices to meet or exceed the rejuvenative effects of enhancing muscle repair, reducing liver adiposity and fibrosis, and increasing hippocampal neurogenesis in old mice, all the key outcomes seen after blood heterochronicity. Comparative proteomic analysis on serum from NBE, and from a similar human clinical procedure of therapeutic plasma exchange (TPE), revealed a molecular re-setting of the systemic signaling milieu, interestingly, elevating the levels of some proteins, which broadly coordinate tissue maintenance and repair and promote immune responses. Moreover, a single TPE yielded functional blood rejuvenation, abrogating the typical old serum inhibition of progenitor cell proliferation. Ectopically added albumin does not seem to be the sole determinant of such rejuvenation, and levels of albumin do not decrease with age nor are increased by NBE/TPE. A model of action (supported by a large body of published data) is that significant dilution of autoregulatory proteins that crosstalk to multiple signaling pathways (with their own feedback loops) would, through changes in gene expression, have long-lasting molecular and functional effects that are consistent with our observations. This work improves our understanding of the systemic paradigms of multi-tissue rejuvenation and suggest a novel and immediate use of the FDA approved TPE for improving the health and resilience of older people.

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Section: Introductionmentioning

confidence: 77%

Rejuvenation of three germ layers tissues by exchanging old blood plasma with saline-albumin

Mehdipour

Skinner

Wong

et al. 2020

Aging

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“…Next, we assessed the capacity of the skin-specific DNAm age predictor to validate the effects of numerous aging-related interventions. Recently, the treatment of cells with the reprogramming factors OCT4, SOX2, KLF4, c-MYC, LIN28, and NANOG (OSKMLN) [ 25 ] was shown to promote a partial reversion in cellular age without altering cellular identity. Here, we applied the skin-specific DNAm age predictor to analyze the published data and observe the effect of the reprogramming treatment on fibroblast DNAm age.…”

Section: Resultsmentioning

confidence: 99%

Highly accurate skin-specific methylome analysis algorithm as a platform to screen and validate therapeutics for healthy aging

Boroni

Zonari²,

Oliveira³

et al. 2020

Clin Epigenet

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Background DNA methylation (DNAm) age constitutes a powerful tool to assess the molecular age and overall health status of biological samples. Recently, it has been shown that tissue-specific DNAm age predictors may present superior performance compared to the pan- or multi-tissue counterparts. The skin is the largest organ in the body and bears important roles, such as body temperature control, barrier function, and protection from external insults. As a consequence of the constant and intimate interaction between the skin and the environment, current DNAm estimators, routinely trained using internal tissues which are influenced by other stimuli, are mostly inadequate to accurately predict skin DNAm age. Results In the present study, we developed a highly accurate skin-specific DNAm age predictor, using DNAm data obtained from 508 human skin samples. Based on the analysis of 2,266 CpG sites, we accurately calculated the DNAm age of cultured skin cells and human skin biopsies. Age estimation was sensitive to the biological age of the donor, cell passage, skin disease status, as well as treatment with senotherapeutic drugs. Conclusions This highly accurate skin-specific DNAm age predictor constitutes a holistic tool that will be of great use in the analysis of human skin health status/molecular aging, as well as in the analysis of the potential of established and novel compounds to alter DNAm age.

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“…The most exciting and potentially impactful technologies to combat COVID-19 and other viral pandemics are those that activate the body's defenses against aging [5,166]. Eventually, with advances in the field, it may even be possible to reverse the age of cells and tissues [171][172][173][174] so that high-risk older individuals can respond to viral infections as though they were young.…”

Section: Agingmentioning

confidence: 99%

Why does COVID-19 disproportionately affect older people?

Mueller

McNamara

Sinclair

2020

Aging

806

678

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The severity and outcome of coronavirus disease 2019 (COVID-19) largely depends on a patient's age. Adults over 65 years of age represent 80% of hospitalizations and have a 23-fold greater risk of death than those under 65. In the clinic, COVID-19 patients most commonly present with fever, cough and dyspnea, and from there the disease can progress to acute respiratory distress syndrome, lung consolidation, cytokine release syndrome, endotheliitis, coagulopathy, multiple organ failure and death. Comorbidities such as cardiovascular disease, diabetes and obesity increase the chances of fatal disease, but they alone do not explain why age is an independent risk factor. Here, we present the molecular differences between young, middle-aged and older people that may explain why COVID-19 is a mild illness in some but life-threatening in others. We also discuss several biological age clocks that could be used in conjunction with genetic tests to identify both the mechanisms of the disease and individuals most at risk. Finally, based on these mechanisms, we discuss treatments that could increase the survival of older people, not simply by inhibiting the virus, but by restoring patients' ability to clear the infection and effectively regulate immune responses.

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Transient non-integrative expression of nuclear reprogramming factors promotes multifaceted amelioration of aging in human cells

Cited by 202 publications

References 41 publications

Rejuvenation of three germ layers tissues by exchanging old blood plasma with saline-albumin

Rejuvenation of three germ layers tissues by exchanging old blood plasma with saline-albumin

Highly accurate skin-specific methylome analysis algorithm as a platform to screen and validate therapeutics for healthy aging

Why does COVID-19 disproportionately affect older people?

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