哺乳动物的某种衰老起因是可逆的

Researchers have discovered a cause of aging in mammals that may be reversible. The essence of this finding is a series of molecular¹ events that enable communication inside cells between the nucleus² and mitochondria（线粒体）. As communication breaks down, aging accelerates. By administering a molecule³ naturally produced by the human body, scientists restored the communication network in older mice. Subsequent tissue samples showed key biological hallmarks that were comparable to those of much younger animals.

 

"The aging process we discovered is like a married couple -- when they are young, they communicate well, but over time, living in close quarters for many years, communication breaks down," said Harvard Medical School Professor of Genetics David Sinclair, senior author on the study. "And just like with a couple, restoring communication solved the problem."

 

This study was a joint⁵ project between Harvard Medical School, the National Institute on Aging, and the University of New South Wales, Sydney, Australia, where Sinclair also holds a position.

 

The findings are published Dec. 19 in Cell.

 

 

Mitochondria are often referred to as the cell's "powerhouse," generating chemical energy to carry out essential biological functions. These self-contained organelles, which live inside our cells and house their own small genomes, have long been identified as key biological players in aging. As they become increasingly dysfunctional（机能失调的） over time, many age-related conditions such as Alzheimer's disease and diabetes⁷ gradually set in.

 

Researchers have generally been skeptical⁸ of the idea that aging can be reversed, due mainly to the prevailing⁹ theory that age-related ills are the result of mutations in mitochondrial DNA¹¹ -- and mutations cannot be reversed.

 

Sinclair and his group have been studying the fundamental science of aging -- which is broadly defined as the gradual decline in function with time -- for many years, primarily focusing on a group of genes¹² called sirtuins. Previous studies from his lab showed that one of these genes, SIRT1, was activated¹³ by the compound resveratrol（白藜芦醇）, which is found in grapes, red wine and certain nuts.

 

Ana Gomes, a postdoctoral scientist in the Sinclair lab, had been studying mice in which this SIRT1 gene⁴ had been removed. While they accurately¹⁴ predicted that these mice would show signs of aging, including mitochondrial dysfunction, the researchers were surprised to find that most mitochondrial proteins coming from the cell's nucleus were at normal levels; only those encoded by the mitochondrial genome were reduced.

 

"This was at odds¹⁵ with what the literature suggested," said Gomes.

 

As Gomes and her colleagues investigated potential causes for this, they discovered an intricate cascade¹⁶ of events that begins with a chemical called NAD and concludes with a key molecule that shuttles information and coordinates¹⁷ activities between the cell's nuclear genome and the mitochondrial genome. Cells stay healthy as long as coordination¹⁸ between the genomes remains¹⁹ fluid. SIRT1's role is intermediary, akin²⁰ to a security guard; it assures that a meddlesome²¹ molecule called HIF-1 does not interfere²² with communication.

 

For reasons still unclear, as we age, levels of the initial chemical NAD decline. Without sufficient NAD, SIRT1 loses its ability to keep tabs on HIF-1. Levels of HIF-1 escalate²³ and begin wreaking²⁴ havoc²⁵ on the otherwise smooth cross-genome communication. Over time, the research team found, this loss of communication reduces the cell's ability to make energy, and signs of aging and disease become apparent.

 

"This particular component²⁶ of the aging process had never before been described," said Gomes.

 

While the breakdown of this process causes a rapid decline in mitochondrial function, other signs of aging take longer to occur. Gomes found that by administering an endogenous compound that cells transform into NAD, she could repair the broken network and rapidly restore communication and mitochondrial function. If the compound was given early enough -- prior to excessive mutation¹⁰ accumulation -- within days, some aspects of the aging process could be reversed.

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