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Chromosomal
mutations and how to obviate them
染色体突变及其排除
There
are two types of accumulating change that happen to our chromosomes as we
age: mutations and epimutations. Mutations are changes to the DNA sequence,
and epimutations are changes to the "decorations" of that DNA which
control its propensity to be decoded into proteins. Luckily, we don't need to
deal with these two phenomena separately, because we can obviate them both in
the same way. 当我们变老时，有两类的积累性变化发生在我们的染色体上：突变和表突变。突变是DNA序列的变化，而表突变是该DNA控制其解码为蛋白质的倾向性的"修饰性"变化。幸运的是，我们不需要单独处理这两类现象，因为我们能够以相同的方法排除它们。 This
is another of the areas of aging in which evolution has done the really hard
work for us. We have an enormous amount of DNA, and the job of keeping it
intact and functional is incredibly complicated. But evolution had to do it,
so it has developed the necessary sophistication for us. 这是老化的另一个领域，进化在其中为我们做了非常艰巨的工作。我们有数量极为庞大的DNA，保持它的完整性和功能性的工作，难以置信地复杂。但是，进化不得不做这项工作，因此，进化为我们发展了必然的复杂化。 We're
particularly lucky in one way: evolution (since the emergence of vertebrates,
anyway) has had one DNA maintenance problem that is far bigger than all the
others, and that is to stop organisms from dying of cancer. 有一个方面我们特别幸运：无论如何，自从出现脊椎动物，进化已经有一个DNA维护问题，它远比其他动物庞大，那就是阻止有机体死于癌症。 Cancer
can kill us even if one cell gets the wrong mutations (or epimutations),
whereas any loss of function in any genes that have nothing to do with cancer
are harmless unless and until they have happened to a lot of the cells in a
given tissue. So, all those genes get a free ride -- they are already maintained
far better than we need them to be in anything like a normal lifetime. 即使一个细胞发生错误的突变（或表突变）而引起癌症，癌症就会杀死我们，然而，任何基因丧失了任何功能但不引起癌症，则是无害的，除非它们已经发生于一个特定组织中的很多细胞。这样，所有基因都获益匪浅--它们被维护得远比我们要它们去做的任何事情（例如，正常寿命）要好得多。 [Note: the above is a slight oversimplification, in
that DNA damage and mutation may be a significant cause of two of the other
problems that SENS seeks to repair, cell depletion and cell toxicity, because
cells can either commit suicide or go into a "senescent"
non-dividing state as a pre-emptive response to DNA damage that stops it
developing into cancer. But these special cases need not concern us here
because they are dealt with by their respective parts of the SENS scheme.] [附注：上述有些过于简单化，其中DNA损伤和突变可能是SENS寻求修补的两个问题（细胞消耗和细胞毒性）的重要原因，因为作为阻止细胞发展为癌症而预先回应于DNA损伤，细胞或者可以预定自杀或者进入"衰老的"非分裂状态。但是，我们这里不必关心这些特殊的例子，因为它们将在SENS方案的各自部分另案处理。] This
means that we don't actually need to fix chromosomal mutations at all in
order to stop them from killing us: all we need to do is develop a really
good cure for cancer. 这意味着，实际上我们完全不必为了阻止它们杀死我们而修理染色体突变：我们需要做的全部事情，是发展一种真正好的方法治愈癌症。 The one that I favour (which was the topic of the third SENS roundtable,
a roundtable meeting I convened in Cambridge in 2002) is called WILT, for
Whole-body Interdiction of Lengthening of Telomeres. This is a very ambitious
but potentially far more comprehensive and long-term approach to combating
cancer than anything currently available or in development: total elimination
of the genes for telomerase and ALT (alternative lengthening of telomeres)
from all of our mitotic cells. 我所喜欢的一个方案称为WILT──在整个身体中阻止端粒变长，这是我于2002年在剑桥召集的一次圆桌会议（the
third SENS roundtable）的题目。这是一次很有雄心的、但比起目前已有的或正在发展中的与癌症战斗任何方法，都潜在地远为广泛和长期的方法：从所有我们有丝分裂细胞中全部剔除端粒酶基因和消除ALT（端粒变长的另一种途径）。 It improves on drug-mediated telomerase inhibition,
because the cancer cell cannot mutate to resist this treatment -- it would
have to create a whole enzyme, telomerase, out of thin air. 它改善了药物介入的端粒酶抑制，因为癌细胞不可能突变来抵抗这种处理──它不能无中生有地创造整个端粒酶。 The idea of course sounds crazy at first hearing,
but it may well be possible, because the technology already exists to
repopulate the stem cells of the blood and (in mice) the gut, and the skin
shouldn't be too tricky either. 当然，这种想法初听起来很疯狂，但它是很可行的，因为已经有了使血和小鼠的肠重新群体化的干细胞技术，使皮肤干细胞重新群体化也不会太难。 The telomere reserve of neonatal stem cells
suffices for about a decade, judging from the age of onset of dyskeratosis
congenita a disease associated with inadequate telomere maintenance. So, in
theory, a decadal repopulation of all our stem cell populations with new ones
whose telomeres had been restored, but which had no telomerase or ALT genes
of their own, should maintain the relevant tissues indefinitely while
preventing any cancer from reaching a life-threatening stage. 从先天性角化不良症（一种端粒维护不当的相关疾病）发作年龄来判断,新生儿的干细胞端粒储备足够满足约10年。因此，在理论上，若我们所有的干细胞群体的端粒已被恢复、但没有端粒酶或自己的ALT基因，那么10年的重新群体化将在长时期内维持相应组织而防止达到威胁一定生命阶段的任何癌症。 Cells already in the body would need either to be
ablated without killing the engineered cells or to have their telomerase and
ALT genes mutated in situ; both approaches are, again, already close to being
technically feasible in mice. 已在身体中的细胞或者需要被除去而不杀死工程化了的细胞，或者需要它们的端粒酶和ATL基因原位突变；在小鼠中这两种方法在技术上都接近于可行。 Talks
on this topic at IABG 10: Aubrey de Grey's
publications on this topic de Grey 在IABG 10上以题目讲话 Aubrey
de Grey以此题目发表文章（Aubrey de Grey's
publications on this topic） |
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