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: 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.”
This study was a joint 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 were published Dec. 19 in
Cell.
When
Sirt1 loses its ability to monitor HIF-1, communication between
mitochondria and the nucleus breaks down, and aging accelerates (credit:
Ana Gomes)
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.
But 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.
Reversing aging by restoring NAD
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.
HIF-1: a cancer-aging 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 certain 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.
The Sinclair lab is funded by the National Institute on Aging
(NIA/NIH), the Glenn Foundation for Medical Research, the Juvenile
Diabetes Research Foundation, the United Mitochondrial Disease
Foundation and a gift from the Schulak family.
Abstract of Cell paper
- A specific decline in mitochondrially encoded genes occurs during aging in muscle
- Nuclear NAD+ levels regulate mitochondrial homeostasis independently of PGC-1α/β
- Declining NAD+ during aging causes pseudohypoxia, which disrupts OXPHOS function
- Raising nuclear NAD+ in old mice reverses pseudohypoxia and metabolic dysfunction
Ever since eukaryotes subsumed the bacterial ancestor of
mitochondria, the nuclear and mitochondrial genomes have had to closely
coordinate their activities, as each encode different subunits of the
oxidative phosphorylation (OXPHOS) system. Mitochondrial dysfunction is a
hallmark of aging, but its causes are debated. We show that, during
aging, there is a specific loss of mitochondrial, but not nuclear,
encoded OXPHOS subunits. We trace the cause to an alternate
PGC-1α/β-independent pathway of nuclear-mitochondrial communication that
is induced by a decline in nuclear NAD
+ and the accumulation
of HIF-1α under normoxic conditions, with parallels to Warburg
reprogramming. Deleting SIRT1 accelerates this process, whereas raising
NAD
+ levels in old mice restores mitochondrial function to
that of a young mouse in a SIRT1-dependent manner. Thus, a pseudohypoxic
state that disrupts PGC-1α/β-independent nuclear-mitochondrial
communication contributes to the decline in mitochondrial function with
age, a process that is apparently reversible.
(¯`*• Global Source and/or more resources at http://goo.gl/zvSV7 │ www.Future-Observatory.blogspot.com and on LinkeIn Group's "Becoming Aware of the Futures" at http://goo.gl/8qKBbK │ @SciCzar │ Point of Contact: www.linkedin.com/in/AndresAgostini
Washington
