Is antagonistic pleiotropy ubiquitous in aging biology?

Lay Summary: An evolutionary mechanism of aging was hypothesized 60 years ago to be the genetic trade-off between early life fitness and late life mortality. Genetic evidence supporting this hypothesis was unavailable then, but has accumulated recently. These tradeoffs, known as antagonistic pleiotropy, are common, perhaps ubiquitous. George Williams' 1957 paper developed the antagonistic pleiotropy hypothesis of aging, which had previously been hinted at by Peter Medawar. Antagonistic pleiotropy, as it applies to aging, hypothesizes that animals possess genes that enhance fitness early in life but diminish it in later life and that such genes can be favored by natural selection because selection is stronger early in life even as they cause the aging phenotype to emerge. No genes of the sort hypothesized by Williams were known 60 years ago, but modern molecular biology has now discovered hundreds of genes that, when their activity is enhanced, suppressed, or turned off, lengthen life and enhance health under laboratory conditions. Does this provide strong support for Williams' hypothesis? What are the implications of Williams' hypothesis for the modern goal of medically intervening to enhance and prolong human health? Here we briefly review the current state of knowledge on antagonistic pleiotropy both under wild and laboratory conditions. Overall, whenever antagonistic pleiotropy effects have been seriously investigated, they have been found. However, not all trade-offs are directly between reproduction and longevity as is often assumed. The discovery that antagonistic pleiotropy is common if not ubiquitous implies that a number of molecular mechanisms of aging may be widely shared among organisms and that these mechanisms of aging can be potentially alleviated by targeted interventions.

通俗摘要：60年前，一种衰老的进化机制被假设为早期生命适应性和晚期生命死亡率之间的遗传权衡。当时没有支持这一假设的遗传学证据，但近年来证据逐渐积累。这些权衡被称为拮抗多效性，很常见，或许无处不在。乔治·威廉姆斯1957年的论文提出了衰老的拮抗多效性假设，彼得·梅达沃此前也曾有所暗示。就衰老而言，拮抗多效性假设认为动物拥有在生命早期增强适应性但在后期降低适应性的基因，并且这些基因可能受到自然选择的青睐，因为在生命早期选择作用更强，即便它们导致衰老表型出现。60年前，威廉姆斯所假设的那种基因还不为人知，但现代分子生物学现在已经发现了数百种基因，当它们的活性被增强、抑制或关闭时，在实验室条件下可以延长寿命并增进健康。这是否为威廉姆斯的假设提供了有力支持呢？威廉姆斯的假设对医学干预以增进和延长人类健康这一现代目标有何影响呢？在此我们简要回顾野生和实验室条件下拮抗多效性的当前知识状况。总体而言，只要认真研究拮抗多效性效应，就会发现它们的存在。然而，并非所有的权衡都像通常所认为的那样直接在繁殖和长寿之间。拮抗多效性即使不是无处不在也是很常见的这一发现意味着，许多衰老的分子机制可能在生物之间广泛共享，并且这些衰老机制可能通过有针对性的干预得到潜在缓解。