X: Great. I am ＜自分の名前＞, working in the ＜所属しているラボのPI＞’s lab as a PhD student in Tokyo. I was really excited about your talk today. Well, actually, I’m looking for a lab for working as a postdoc. Do you mind talking to me for a couple of minutes?
オックスフォード大学の場合、transfer of status viva／confirmation of status viva（それぞれアメリカのqualifying / preliminary examに相当）という中間試験があり、事情が認められれば、confirmationの時期を延長することも可能ですが、confirmationをとったら1年間で博士論文を書き上げるというシステムになっているようです。
Sinclair博士のラボから2018年に発表された論文「Impairment of an endothelial NAD+-H2S signaling network is a reversible cause of vascular aging 血管内皮におけるNAD+H2Sシグナル経路の脆弱化が血管老化の可逆的な原因である（Das et al. 2018 Cell 173, 74-89)」を読んだのですが、とても読みやすいイントロダクションで、幅広い読者を飽きさせない言い回しや、すっきりした論理の組み立てが印象的でした。
One of the most profound changes to the body as it ages is a decline in the number and function of endothelial cells (ECs) that line the vasculature. The performance of organs and tissues is critically dependent on a functional microcapillary network that maintains a supply of oxygen, exchanges heat and nutrients, and removes waste products. According to the Vascular Theory of Aging, vascular decline is one of the major causes of aging and age-related diseases.
Das et al. 2018 Cell 173, 74-89
The most significant bodily change that occurs as we age is the reduction and loss of function of the endothelial cells that line the vascular system.
Despite the importance of capillary loss to human health, it is surprising how little we understand about its underlying causes.Exercise is currently the best way to delay the effects of aging on the microvasculature by promoting neovascularization, but little is known about why tissues become desensitized to exercise with age. Skeletal muscle is an ideal tissue to study the effects of aging on neovascularization and capillary maintenance. For reasons that are unclear, as we age there is an increase in muscle EC apoptosis, decreased neovascularization, and blood vessel loss, resulting in reduced muscle mass (sarcopenia) and a decline in strength and endurance in the later decades of life, even with exercise. A few exercise-mimetic agents have been reported that increase mitochondrial function (e.g., resveratrol and PPARδ agonists), none of which are known to work by increasing capillary density or blood flow. SIRT1 is a member of the sirtuin family of NAD+-dependent deacylases that mediate the health benefits of dietary restriction (DR) and can extend lifespan when overexpressed. In young muscle, SIRT1 is required for ischemia-induced neovascularization, vascular relaxation, and is implicated in EC senescence.It is, however, unknown whether endothelial SIRT1 regulates microvascular remodeling in skeletal muscle tissue, and if so, whether its breakdown with age is cell-autonomous or reversible.
SIRT1-activating compounds (STACs) such as resveratrol and SRT1720 have been pursued as a strategy for ameliorating age-related diseases. A more recent approach has been to restore NAD+levels by treating with NAD precursors such as nicotinamide riboside (NR) or nicotinamide mononucleotide (NMN). NAD precursors increase the angiogenic capacity of ECs in cell culture, improve the exercise capacity of young mice, and protect against age-related physiological decline including reduced DNA repair, mitochondrial dysfunction, and glucose intolerance. Whether a decrease in NAD+ and SIRT1 activity in ECs is a cause of microvasculature loss and frailty during aging is not yet known.
Another DR mimetic is hydrogen sulfide (H2S), a gas generated endogenously by cystathionine β-synthase (CBS) and/or cystathionine γ-lyase (CSE).Evidence indicates that SIRT1 and H2S may lie in the same pathway.For example, in Caenorhabditis elegans, hydrogen sulfide (H2S) extends lifespan in a Sir2.1-dependent manner. In mammals, ectopic treatment with H2S induces SIRT1 in response to oxidative stress and protects rat hearts from ischemia/reperfusion via a mechanism requiring SIRT1.
In this study, we tested whether a decline in SIRT1 activity in ECs is a major reason why blood flow and endurance decrease with age, and whether SIRT1 stimulation by NMN and/or H2S can reverse these changes. We show that loss of endothelial SIRT1 results in an early decline in skeletal muscle vascular density and exercise capacity, while overexpression of endothelial SIRT1 has a protective effect, ostensibly by sensitizing ECs to vascular endothelial growth factor (VEGF) coming from muscle fibers. Pharmacologically raising NAD+ levels promotes muscle vascular remodeling following ischemic injury and restores capillary density and treadmill endurance of old mice back to youthful levels, and in young mice during chronic exercise, an effect that is further augmented by H2S.
先程、少し触れましたが、第5段落においてリサーチクエスチョンと結果が示されているものの、手法についての記載があまりありません。本論文のウリは手法の新規性ではなく、今あるテクニックを駆使してサーチュイン遺伝子のスイッチを入れることによりマウスを人工的に若がえらせることができた、という成果にあるのです。その道の研究者であれば、成果を見ただけで手法を予想できますし、専門外の読者であれば手法には興味がないか、興味があればmaterials and methodsを読むでしょう。