Vascular rejuvenation is geroprotective

doi:10.1126/science.abj8674

GSTDTAP > 气候变化

DOI	10.1126/science.abj8674
	Vascular rejuvenation is geroprotective
	Hellmut G. Augustin; Jonathan Kipnis
	2021-07-30
发表期刊	Science
出版年	2021
英文摘要	The scientific perception of blood vessels has changed substantially in recent years. They are no longer considered passive conduits of blood that respond to exogenous cues. Now, the vascular endothelium is considered to act as an instructive gatekeeper to actively control organ function ([ 1 ][1]). Although mechanisms of local regulation by the vasculature have been identified for most organs and many disease states, including cancer, the study of systemic instructive vascular signaling is still in its infancy. On page 533 of this issue, Grunewald et al. ([ 2 ][2]) report that low-dose systemic increase of vascular endothelial growth factor–A (VEGFA) in the circulation leads to a notable life span extension in mice. The complex multiorgan rejuvenation phenotype of these mice yields insight into the mechanisms of organism aging and highlights the critical role of the vasculature as a gatekeeper of life span and health span. Among the molecular mechanisms that control longevity, metabolism is best studied and recognized as a major determinant of life span ([ 3 ][3]). Cellular and organismic metabolism is heavily influenced by food intake. Indeed, profound effects of caloric restriction on the longevity of rats were identified in the 1930s ([ 4 ][4]). These early findings have more recently also been validated in rhesus macaques ([ 5 ][5]). Blood vessels appear to be another major determinant of life span. Seventeenth-century British surgeon Thomas Sydenham coined the phrase “A man is as old as his arteries” ([ 6 ][6]). Although this statement primarily referred to declining elasticity of large arteries, including the aorta, microvascular aging is similarly believed to contribute to organismal aging. The study of Grunewald et al. may have unraveled the molecular mechanism for the vascular control of life span. The authors generated mice that conditionally overexpress systemic VEGFA in the circulation (produced in the liver) at 1.5- to maximally twofold above baseline from early adulthood. The mice had a substantially increased median life span, up to 48% in male mice and 39% in female mice. Although this may be among the highest ever reported percentage increase in mammalian life span ([ 7 ][7]), some caution needs to be exerted because the authors used a mixed mouse strain with a relatively low median life expectancy of ∼22 months [median life expectancy of different strains of laboratory mice varies between 18 and 32 months; pure C57Bl/6J mice have a median life expectancy of ∼28 months ([ 7 ][7])]. Nevertheless, low-dose systemic VEGFA overexpression extended median life expectancy in these mice to a noteworthy 33 months in male mice and 31 months in female mice. ![Figure][8] Multiorgan rejuvenation Mildly increased concentrations of circulating vascular endothelial growth factor–A (VEGFA), produced in the liver, leads to a considerable life span extension of mice. As they age, these mice display a complex multiorgan phenotype that collectively results in systemic rejuvenation. GRAPHIC: N. DESAI/ SCIENCE VEGFA is best known for its ability to act as a master regulator of the angiogenic cascade, critically controlling developmental and pathological blood vessel formation in the adult, including tumor angiogenesis ([ 8 ][9]). It initiates the sprouting of new capillaries from preexisting capillaries through its motogenic and mitogenic effects elicited through VEGF receptors, which are almost exclusively expressed by endothelial cells. However, VEGFA is also a survival factor for immature blood vessels. Albeit not widely appreciated, vascular rarefaction, the reduction of tissue microvessel density, has been observed in the cutaneous vasculature as a side effect of systemic anti-angiogenic therapy ([ 9 ][10]), suggesting critical maintenance functions of VEGFA on the existing vasculature. Grunewald et al. discovered an increasing VEGFA signaling insufficiency in aged mice as a result of rising circulating concentrations of the VEGFA decoy receptor sVEGF-R1 (also called sFlt1). Soluble Flt1 is an endogenous antagonist of VEGFA signaling that, for example, is involved in maintaining avascularity of the cornea ([ 10 ][11]). The molecular mechanism underlying the gradual rise in circulating sFlt1 is not known but appears to be responsible for aging, as evidenced by the life span extension of mice overexpressing VEGFA. These mice displayed during aging a complex multiorgan phenotype that collectively resulted in systemic rejuvenation elicited by mildly increased concentrations of vasculotropic VEGFA (see the figure). Low-dose VEGFA overexpression may be sufficient to override the neutralizing effect of the decoy receptor sFlt1. Grunewald et al. observed in wild-type mice a steady increase of circulating VEGFA over their life spans. This could be interpreted as a physiological counterregulatory mechanism to compensate for the increased concentrations of the decoy receptor. Building on this hypothesis, the transgenic approach of the study could mechanistically be interpreted as subtly overriding the insufficient endogenous counterregulatory process. The molecular regulators of vessel function are identical between mice and humans. Thus, could these mechanisms also be operating in humans? A recent study profiled the concentration of more than 2000 proteins in the circulation over the life span of humans ([ 11 ][12]). VEGFA is among those molecules whose circulating concentrations are substantially regulated over the life span: A subtle, but continuous increase of circulating VEGFA between 25 and 75 years of age is followed by a sharp increase in circulating amounts after 75 years of age ([ 11 ][12]). Most intriguingly, VEGFA cooperates with angiopoietin-2, which acts as a contextual agonistic and antagonistic ligand for the receptor tyrosine kinase TIE2 (angiopoietin-1 receptor), which controls vessel maturation. Angiopoietin-2 similarly shows a sharp increase in the circulation after 75 years of age ([ 11 ][12]). How can a single vasculotropic factor exert such diverse effects in different organs? Reducing vascular rarefaction will lead to improved organ perfusion, which alone may be sufficient to positively affect homeostatic organ function. Yet, it remains unknown whether this would be sufficient to explain the multitude of different phenotypes. The most compelling common denominator among the different phenotypes may be a complex systemic metabolic reprogramming that could account for many of the different organ phenotypes observed by Grunewald et al. Similarly, chronic systemic inflammation appears to be an important contributor to organismal aging (called “inflammaging”) and also to cancer development ([ 12 ][13]). Reducing chronic inflammation through improved vascular VEGFA signaling may be another important common denominator of the observed plethora of phenotypes, including the reduction in tumor burden in these aged mice. How VEGFA overexpression affects the immune system warrants further investigation. Several aspects of the immune system are associated with aging ([ 13 ][14]), notably shrinkage of the naïve T cell compartment. T cell production in the thymus declines with age—a process that might be slowed down by reduced vascular rarefaction of the thymus. The brain also relies on vascular health to function correctly, and slowed aging of the brain may underlie ameliorated aging of other bodily tissues ([ 14 ][15]). Although Grunewald et al. did not assess the impact of VEGFA overexpression on brain health, a role of the brain in determining aging of the body could be an exciting future frontier of research. Grunewald et al. used a genetic approach of VEGFA overexpression that likely reflects a preventive regimen. The study includes some experiments with induced expression of VEGFA only in adult mice. Yet, it remains unclear whether the effects on life span elicited by low-level systemic VEGFA overexpression from early adulthood could also be elicited in a therapeutic setting when given to aging mice. An important conceptual question not answered by the study of Grunewald et al. is whether low-dose systemic VEGFA overexpression directly alters the aging process or whether it positively interferes with deficiencies in the environment or in the genetic makeup of the particular mouse strain that lead to aging. This question, often ignored, applies to essentially all experimental longevity studies and warrants careful consideration ([ 7 ][7]). The relatively short life span of the control mice used in the study makes it likely that interference with deficiencies rather than direct alterations of the aging process may causally be involved in the observed phenotypes. Yet, this may not be a limitation of the study but rather part of its strength, because it emphasizes the idea that blood vessels probably do not affect the aging process per se but enable healthy aging. Maintaining physiological function of blood vessels throughout life may therefore be among the most promising strategies in the long run to achieve maximum human life span and optimize health span. This may possibly be achieved with preventive or therapeutic approaches. Likewise, the effects of lifestyle (for example, exercise) in preventing vascular aging deserve intensified analysis. 1. [↵][16]1. S. Rafii, 2. J. M. Butler, 3. B.-S. Ding , Nature 529, 316 (2016). [OpenUrl][17][CrossRef][18][PubMed][19] 2. [↵][20]1. M. Grunewald et al ., Science 373, eabc8479 (2021). [OpenUrl][21][Abstract/FREE Full Text][22] 3. [↵][23]1. C. López-Otín, 2. L. Galluzzi, 3. J. M. P. Freije, 4. F. Madeo, 5. G. Kroemer , Cell 166, 802 (2016). [OpenUrl][24][CrossRef][25][PubMed][26] 4. [↵][27]1. A. Di Francesco, 2. C. Di Germanio, 3. M. Bernier, 4. R. de Cabo , Science 362, 770 (2018). [OpenUrl][28][Abstract/FREE Full Text][29] 5. [↵][30]1. J. A. Mattison et al ., Nat. Commun. 8, 14063 (2017). 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领域	气候变化 ; 资源环境
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文献类型	期刊论文
条目标识符	http://119.78.100.173/C666/handle/2XK7JSWQ/335531
专题	气候变化资源环境科学
推荐引用方式 GB/T 7714	Hellmut G. Augustin,Jonathan Kipnis. Vascular rejuvenation is geroprotective[J]. Science,2021.
APA	Hellmut G. Augustin,&Jonathan Kipnis.(2021).Vascular rejuvenation is geroprotective.Science.
MLA	Hellmut G. Augustin,et al."Vascular rejuvenation is geroprotective".Science (2021).