神經(jīng)元壽命不受原有宿主壽命限制

最近，意大利帕維亞大學(xué)和都靈大學(xué)的科學(xué)家通過實(shí)驗(yàn)證明，神經(jīng)元的壽命不受生物最大壽命極限的限制，但它必須被移植到一個(gè)壽命更長的宿主身上，此時(shí)它的壽命能超過原來生物的壽命持續(xù)下去。相關(guān)論文發(fā)表在美國《國家科學(xué)院學(xué)報(bào)》上。

帕維亞大學(xué)的洛倫佐·馬格雷希和同事利用一種腦細(xì)胞移植技術(shù)，在胸腺發(fā)育完成之前就把小鼠胚胎的小腦前體移植到另一種壽命更長的大鼠腦中，大鼠腦部正處于發(fā)育期。結(jié)果發(fā)現(xiàn)，移植到大鼠腦中的小鼠神經(jīng)元能存活3年之久，這是小鼠平均壽命的兩倍。

小腦神經(jīng)元的樹突、樹突棘和突觸會隨正常老化而大量損失。馬格雷希說：“我們移植了小鼠的浦肯野細(xì)胞（Purkinje Cell），以確定樹突棘密度降低的速率究竟是跟小鼠還是大鼠自身的浦肯野細(xì)胞一樣?！逼挚弦凹?xì)胞是從小腦皮質(zhì)發(fā)出的唯一能傳出沖動的神經(jīng)元，有許多擴(kuò)展分支?！敖Y(jié)果表明，移植細(xì)胞的老化性樹突棘損失速度變得更慢，和壽命更長的大鼠一樣，相比于小鼠的老化而言，這達(dá)到了一種不受限制的水平?！?/p>

研究人員指出，這表明神經(jīng)元的存活和老化是同時(shí)發(fā)生的，但卻是各自獨(dú)立的過程，延長機(jī)體壽命未必會導(dǎo)致大腦的最終耗竭。這為通過飲食、運(yùn)動和藥物干預(yù)等措施來延長生物壽命帶來了更多希望。

馬格雷希說，即使考慮了明顯的種間差異，實(shí)驗(yàn)結(jié)果也能推廣到人類和其他壽命更長的物種身上。通過延長平均生物壽命的方法來延長生命，不一定會出現(xiàn)生物在其壽命還很長時(shí)，腦中神經(jīng)元就已所剩無幾的情況。

研究小組還打算從蛋白質(zhì)組水平實(shí)施宿主和移植細(xì)胞的顯微切割，以研究是什么原因?qū)е铝藰渫患瑩p失變慢。馬格雷希指出：“如果能發(fā)現(xiàn)某個(gè)或某些因素導(dǎo)致了這些變化，就有希望開發(fā)出更有效的藥物，治療所有病理性神經(jīng)組織退化。這種退化開始于突觸連接減少，在生物壽命結(jié)束前神經(jīng)元就已經(jīng)死了?！彼麄冞€在用不同種系的轉(zhuǎn)基因小鼠實(shí)驗(yàn)異種移植，這些小鼠的老化路徑已經(jīng)被改變。

Separate lives: Neuronal and organismal lifespans decoupled

Replicati ve aging (also known as replicative senescence) causes mammalian cells to undergo a process of growth arrest dependent on telomeres (the shortening of repeated sequences at the ends of chromosomes). Neurons, on the other hand, are exempt from aging,and so the questi on of their actual lifespan has remained unanswered.Recently, however, scientists at the University of Pavia and the University of Turin demonstrated that neuronal lifespan is not limited by the organism's maximum lifespan but, remarkably, conti nues when transplanted in a longer-living host. The researchers accomplished this by transplanting embryonic mouse cerebellar precursors into the developing brain of longer-living rats, in which the grafted mouse neurons survived for up to three years – twice the average lifespan of the donor mice.

Dr. Lorenzo Magrassi discussed the challenges he and his colleagues, Dr. Ketty Leto and Dr. Ferdinando Rossi,encountered in their research."Cell transplantation into the developing rat brain is a technique that was originally developed by us and other research groups in the early nineties of the last century,"Magrassi tells Medical Xpress. "In recent years, we improved the protocol that, now standardized,allows reliable implantation rates with good survival rates." While not all implanted embryos develop into adult animals carrying a viable transplant, Magrassi adds,the percentage of those that do is sufficient to plan a long-term survival experiment involving roughly 100 such successfully-born animals.

In addressing these challenges, Magrassi says that together with the intrinsic bonus of studying cells inside the nervous system, which is immunoprivileged,they transplanted cells before development of the thymus (a specialized organ of the immune system) was complete. The latter can help induce immunological tolerance in the host to the engraft ed cells.

One remaining question is if their research can potentially be extended to determine whether or not a maximum lifespan exists for any postmitotic mammalian cells – Including neurons. "Similar techniques can, in principle,be extended to other organs containing perennial cells,"Magrassi notes, "but we don't have direct experience with injecting cells into organs outside of the central nervous system." Since the central nervous system is privileged compared to other organs that are more prone to immunological surveillance and attack, a major problem when transferring their experimental paradigm to other organs, he explains, could be an increase in immunological problems.

The scientists say their results suggest that neuronal survival and aging are coincidental but separable processes, thus increasing the hope that extending organismal lifespan by dietary,behavioral, and pharmacologic interventions will not necessarily result in a neuronally depleted brain. "Even after taking into account the obvious species differences, our results in rodents can be extrapolated by analogy to humans and other longerliving species where this sort of experiment is impossible," Magrassi explains. "Our fi ndings suggest that extending life by extending average organismal lifespan – a hallmark of all technologically advanced societi es – will not necessarily result in neuron-impoverished brains well before the longer-living individual dies." This bodes well for those studying life extension: Their eff orts are not intrinsically futi le, Magrassi notes, because in the absence of pathology, prolonging life span does not necessarily mean dementia due to widespread loss of neurons,as many people sti ll think.