Naturally Produced Compound Rewinds Aspects of Age-Related Demise in Mice
 |
| Sirt1 protein, red, circles the cell's chromosomes, blue. (Credit: Ana Gomes) |
Researchers have
discovered a cause of aging in mammals that may be reversible.
The essence of this
finding is a series of molecular events that enable communication inside cells
between the nucleus and mitochondria. As communication breaks down, aging
accelerates.
By administering a molecule 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."
The findings are
published Dec. 19 in Cell.
Communication
breakdown
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 over time, many age-related conditions such as Alzheimer's
disease and diabetes gradually set in.
Researchers have
generally been skeptical of the idea that aging can be reversed, due mainly to
the prevailing theory that age-related ills are the result of mutations in
mitochondrial DNA -- 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 genes called sirtuins. Previous studies from his lab
showed that one of these genes, SIRT1, was activated by the compound
resveratrol, 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 gene
had been removed. While they accurately 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 odds
with what the literature suggested," said Gomes.
As Gomes and her
colleagues investigated potential causes for this, they discovered an intricate
cascade of events that begins with a chemical called NAD and concludes with a
key molecule that shuttles information and coordinates activities between the cell's
nuclear genome and the mitochondrial genome. Cells stay healthy as long as
coordination between the genomes remains fluid.
SIRT1's role is intermediary,
akin to a security guard; it assures that a meddlesome molecule called HIF-1
does not interfere 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
escalate and begin wreaking havoc 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
component 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 mutation accumulation -- within days,
some aspects of the aging process could be reversed.
Cancer connection
Examining muscle from
two-year-old mice that had been given the NAD-producing compound for just one
week, the researchers looked for indicators of insulin resistance, inflammation
and muscle wasting. In all three instances, tissue from the mice resembled that
of six-month-old mice. In human years, this would be like a 60-year-old
converting to a 20-year-old in these specific areas.
One particularly
important aspect of this finding involves HIF-1. More than just an intrusive
molecule that foils communication, HIF-1 normally switches on when the body is
deprived of oxygen.
Otherwise, it remains silent. Cancer, however, is known to
activate and hijack HIF-1. Researchers have been investigating the precise role
HIF-1 plays in cancer growth.
"It's certainly
significant to find that a molecule that switches on in many cancers also
switches on during aging," said Gomes. "We're starting to see now
that the physiology of cancer is in certain ways similar to the physiology of
aging. Perhaps this can explain why the greatest risk of cancer is age. "
"There's clearly
much more work to be done here, but if these results stand, then many aspects
of aging may be reversible if caught early," said Sinclair.
The researchers are now
looking at the longer-term outcomes of the NAD-producing compound in mice and
how it affects the mouse as a whole. They are also exploring whether the
compound can be used to safely treat rare mitochondrial diseases or more common
diseases such as Type 1 and Type 2 diabetes. Longer term, Sinclair plans to
test if the compound will give mice a healthier, longer life.
Story Source:
The above story is based
on materials provided by Harvard Medical School.
The original article was written by David Cameron.
Note: Materials may
be edited for content and length. For further information, please contact the
source cited above.
Journal Reference:
1.
Ana P. Gomes, Nathan L. Price, Alvin J.Y. Ling,
Javid J. Moslehi, Magdalene K. Montgomery, Luis Rajman, James P.
White, João S. Teodoro, Christiane D. Wrann, Basil P. Hubbard,
Evi M. Mercken, Carlos M. Palmeira, Rafael de Cabo,
Anabela P. Rolo, Nigel Turner, Eric L. Bell, David A. Sinclair. Declining NAD Induces a
Pseudohypoxic State Disrupting Nuclear-Mitochondrial Communication during Aging. Cell, 2013; 155 (7): 1624
DOI:10.1016/j.cell.2013.11.037
