Karl N. Miller,1,6 Stella G. Victorelli,2,3,6 Hanna Salmonowicz,2,3,4,5 Nirmalya Dasgupta,1 Tianhui Liu,1 Joa˜o F. Passos,2,3,* and Peter D. Adams1,* 1Aging, Cancer and Immuno-oncology Program, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA 92037, USA 2Department of Physiology and Biomedical Engineering, Mayo Clinic, Rochester, MN 55905, USA 3Robert and Arlene Kogod Center on Aging, Mayo Clinic, Rochester, MN 55905, USA 4Institute for Cell and Molecular Biosciences & Newcastle University Institute for Ageing, Newcastle upon Tyne NE4 5PL, UK 5International Institute of Molecular Mechanisms and Machines, Polish Academy of Sciences, 02-109 Warsaw, Poland 6These authors contributed equally

*Correspondence: 该Email地址已收到反垃圾邮件插件保护。要显示它您需要在浏览器中启用JavaScript。 (J.F.P.), 该Email地址已收到反垃圾邮件插件保护。要显示它您需要在浏览器中启用JavaScript。 (P.D.A.)

https://doi.org/10.1016/j.cell.2021.09.034

SUMMARY

      Endogenous cytoplasmic DNA (cytoDNA) species are emerging as key mediators of inflammation in diverse physiological and pathological contexts. Although the role of endogenous cytoDNA in innate immune activation is well established, the cytoDNA species themselves are often poorly characterized and difficult to distinguish, and their mechanisms of formation, scope of function and contribution to disease are incompletely understood. Here, we summarize current knowledge in this rapidly progressing field with emphases on similarities and differences between distinct cytoDNAs, their underlying molecular mechanisms of formation and function, interactions between cytoDNA pathways, and therapeutic opportunities in the treatment of age-associated diseases.

Graphical abstract

Highlights

 Hepatocyte-specific 4F expression induces cell proliferation and dedifferentiation

 Hepatocyte-specific 4F expression induces a global change in DNA accessibility

 Top2a is required for cellular reprogramming in vitro and in vivo

 In vivo reprogramming has beneficial effects on regenerative capacity

Authors

Tomoaki Hishida, Mako Yamamoto,

Yuriko Hishida-Nozaki, ...,

Pradeep Reddy, Guang-Hui Liu,

Juan Carlos Izpisua Belmonte

Correspondence

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In brief

In regenerating animals, such as fish and salamanders, dedifferentiation followed by proliferation contributes to tissue regeneration. Hishida et al. show that hepatocyte-specific cellular reprogramming induces cell proliferation and dedifferentiation in the liver and enhances liver regenerative capacity through topoisomerase2-mediated partial reprogramming.

SUMMARY

      Mammals have limited regenerative capacity, whereas some vertebrates, like fish and salamanders, are able to regenerate their organs efficiently. The regeneration in these species depends on cell dedifferentiation followed by proliferation. We generate a mouse model that enables the inducible expression of the four Yamanaka factors (Oct-3/4, Sox2, Klf4, and c-Myc, or 4F) specifically in hepatocytes. Transient in vivo 4F expression induces partial reprogramming of adult hepatocytes to a progenitor state and concomitantly increases cell proliferation. This is indicated by reduced expression of differentiated hepatic-lineage markers, an increase in markers of proliferation and chromatin modifiers, global changes in DNA accessibility, and an acquisition of liver stem and progenitor cell markers. Functionally, short-term expression of 4F enhances liver regenerative capacity through topoisomerase2-mediated partial reprogramming. Our results reveal that liver-specific 4F expression in vivo induces cellular plasticity and counteracts liver failure, suggesting that partial reprogramming may represent an avenue for enhancing tissue regeneration.

SUMMARY

      We conducted a double-blinded phase I clinical trial to establish whether nicotinamide adenine dinucleotide (NAD) replenishment therapy, via oral intake of nicotinamide riboside (NR), is safe, augments cerebral NAD levels, and impacts cerebral metabolism in Parkinson’s disease (PD). Thirty newly diagnosed, treatmentnaive patients received 1,000 mg NR or placebo for 30 days. NR treatment was well tolerated and led to a significant, but variable, increase in cerebral NAD levels—measured by 31phosphorous magnetic resonance spectroscopy—and related metabolites in the cerebrospinal fluid. NR recipients showing increased brain NAD levels exhibited altered cerebral metabolism, measured by 18fluoro-deoxyglucose positron emission to mography, and this was associated with mild clinical improvement. NR augmented the NAD metabolome and induced transcriptional upregulation of processes related to mitochondrial, lysosomal, and proteasomal function in blood cells and/or skeletal muscle. Furthermore, NR decreased the levels of inflammatory cytokines in serum and cerebrospinal fluid. Our findings nominate NR as a potential neuroprotective therapy for PD, warranting further investigation in larger trials.

SUMMARY

      Mitochondrial function declines during brain aging and is suspected to play a key role in age-induced cognitive decline and neurodegeneration. Supplementing levels of spermidine, a body-endogenousmetabolite, has been shown to promote mitochondrial respiration and delay aspects of brain aging. Spermidine serves as the aminobutyl group donor for the synthesis of hypusine (Nε -[4-amino-2-hydroxybutyl]-lysine) at a specific lysine residue of the eukaryotic translation initiation factor 5A (eIF5A). Here, we show that in the Drosophila brain, hypusinated eIF5A levels decline with age but can be boosted by dietary spermidine. Several genetic regimes of attenuating eIF5A hypusination all similarly affect brain mitochondrial respiration resembling age-typical mitochondrial decay and also provoke a premature aging of locomotion and memory formation in adult Drosophilae. eIF5A hypusination, conserved through all eukaryotes as an obviously critical effector of spermidine, might thus be an important diagnostic and therapeutic avenue in aspects of brain aging provoked by mitochondrial decline.