Tag Archives: mitochondria

Pass the Nicotinamide Adenine Dinucleotide

NAD-moleculeFor those of us seeking to live another 100 years or more the news and/or hype over the last decade belonged to resveratrol. The molecule is believed to improve functioning of specific biochemical pathways in the cell, which may improve cell repair and hinder the aging process. Resveratrol is found — in trace amounts — in grape skin (and hence wine), blueberries and raspberries. While proof remains scarce, this has not stopped the public from consuming large quantities of wine and berries.

Ironically, one would need to ingest such large amounts of resveratrol to replicate the benefits found in mice studies, that the wine alone would probably cause irreversible liver damage before any health benefits appeared. Oh well.

So, on to the next big thing, since aging cannot wait. It’s called NAD or Nicotinamide Adenine Dinucleotide. NAD performs several critical roles in the cell, one of which is energy metabolism. As we age our cells show diminishing levels of NAD and this is, possibly, linked to mitochondrial deterioration. Mitochondria are the cells’ energy factories, so keeping our mitochondria humming along is critical. Thus, hordes of researchers are now experimenting with NAD and related substances to see if they hold promise in postponing cellular demise.

From Scientific American:

Whenever I see my 10-year-old daughter brimming over with so much energy that she jumps up in the middle of supper to run around the table, I think to myself, “those young mitochondria.”

Mitochondria are our cells’ energy dynamos. Descended from bacteria that colonized other cells about 2 billion years, they get flaky as we age. A prominent theory of aging holds that decaying of mitochondria is a key driver of aging. While it’s not clear why our mitochondria fade as we age, evidence suggests that it leads to everything from heart failure to neurodegeneration, as well as the complete absence of zipping around the supper table.

Recent research suggests it may be possible to reverse mitochondrial decay with dietary supplements that increase cellular levels of a molecule called NAD (nicotinamide adenine dinucleotide). But caution is due: While there’s promising test-tube data and animal research regarding NAD boosters, no human clinical results on them have been published.

NAD is a linchpin of energy metabolism, among other roles, and its diminishing level with age has been implicated in mitochondrial deterioration. Supplements containing nicotinamide riboside, or NR, a precursor to NAD that’s found in trace amounts in milk, might be able to boost NAD levels. In support of that idea, half a dozen Nobel laureates and other prominent scientists are working with two small companies offering NR supplements.

The NAD story took off toward the end of 2013 with a high-profile paper by Harvard’s David Sinclair and colleagues. Sinclair, recall, achieved fame in the mid-2000s for research on yeast and mice that suggested the red wine ingredient resveratrol mimics anti-aging effects of calorie restriction. This time his lab made headlines by reporting that the mitochondria in muscles of elderly mice were restored to a youthful state after just a week of injections with NMN (nicotinamide mononucleotide), a molecule that naturally occurs in cells and, like NR, boosts levels of NAD.

It should be noted, however, that muscle strength was not improved in the NMN-treated micethe researchers speculated that one week of treatment wasn’t enough to do that despite signs that their age-related mitochondrial deterioration was reversed.

NMN isn’t available as a consumer product. But Sinclair’s report sparked excitement about NR, which was already on the market as a supplement called Niagen. Niagen’s maker, ChromaDex, a publicly traded Irvine, Calif., company, sells it to various retailers, which market it under their own brand names. In the wake of Sinclair’s paper, Niagen was hailed in the media as a potential blockbuster.

In early February, Elysium Health, a startup cofounded by Sinclair’s former mentor, MIT biologist Lenny Guarente, jumped into the NAD game by unveiling another supplement with NR. Dubbed Basis, it’s only offered online by the company. Elysium is taking no chances when it comes to scientific credibility. Its website lists a dream team of advising scientists, including five Nobel laureates and other big names such as the Mayo Clinic’s Jim Kirkland, a leader in geroscience, and biotech pioneer Lee Hood. I can’t remember a startup with more stars in its firmament.

A few days later, ChromaDex reasserted its first-comer status in the NAD game by announcing that it had conducted a clinical trial demonstrating that a single dose of NR resulted in statistically significant increases in NAD in humansthe first evidence that supplements could really boost NAD levels in people. Details of the study won’t be out until it’s reported in a peer-reviewed journal, the company said. (ChromaDex also brandishes Nobel credentials: Roger Kornberg, a Stanford professor who won the Chemistry prize in 2006, chairs its scientific advisory board. Hes the son of Nobel laureate Arthur Kornberg, who, ChromaDex proudly notes, was among the first scientists to study NR some 60 years ago.)

The NAD findings tie into the ongoing story about enzymes called sirtuins, which Guarente, Sinclair and other researchers have implicated as key players in conferring the longevity and health benefits of calorie restriction. Resveratrol, the wine ingredient, is thought to rev up one of the sirtuins, SIRT1, which appears to help protect mice on high doses of resveratrol from the ill effects of high-fat diets. A slew of other health benefits have been attributed to SIRT1 activation in hundreds of studies, including several small human trials.

Here’s the NAD connection: In 2000, Guarente’s lab reported that NAD fuels the activity of sirtuins, including SIRT1the more NAD there is in cells, the more SIRT1 does beneficial things. One of those things is to induce formation of new mitochondria. NAD can also activate another sirtuin, SIRT3, which is thought to keep mitochondria running smoothly.

Read the entire article here.

Image: Structure of nicotinamide adenine dinucleotide, oxidized (NAD+). Courtesy of Wikipedia. Public Domain.

The Inevitability of Life: A Tale of Protons and Mitochondria

A fascinating article by Nick Lane a leading researcher into the origins of life. Lane is a Research Fellow at University College London.

He suggests that it would be surprising if simple, bacterial-like, life were not common throughout the universe. However, the acquisition of one cell by another — an event that led to all higher organisms on planet Earth, is an altogether much rarer occurrence. So are we alone in the universe?

[div class=attrib]From the New Scientist:[end-div]

UNDER the intense stare of the Kepler space telescope, more and more planets similar to our own are revealing themselves to us. We haven’t found one exactly like Earth yet, but so many are being discovered that it appears the galaxy must be teeming with habitable planets.

These discoveries are bringing an old paradox back into focus. As physicist Enrico Fermi asked in 1950, if there are many suitable homes for life out there and alien life forms are common, where are they all? More than half a century of searching for extraterrestrial intelligence has so far come up empty-handed.

Of course, the universe is a very big place. Even Frank Drake’s famously optimistic “equation” for life’s probability suggests that we will be lucky to stumble across intelligent aliens: they may be out there, but we’ll never know it. That answer satisfies no one, however.

There are deeper explanations. Perhaps alien civilisations appear and disappear in a galactic blink of an eye, destroying themselves long before they become capable of colonising new planets. Or maybe life very rarely gets started even when conditions are perfect.

If we cannot answer these kinds of questions by looking out, might it be possible to get some clues by looking in? Life arose only once on Earth, and if a sample of one were all we had to go on, no grand conclusions could be drawn. But there is more than that. Looking at a vital ingredient for life – energy – suggests that simple life is common throughout the universe, but it does not inevitably evolve into more complex forms such as animals. I might be wrong, but if I’m right, the immense delay between life first appearing on Earth and the emergence of complex life points to another, very different explanation for why we have yet to discover aliens.

Living things consume an extraordinary amount of energy, just to go on living. The food we eat gets turned into the fuel that powers all living cells, called ATP. This fuel is continually recycled: over the course of a day, humans each churn through 70 to 100 kilograms of the stuff. This huge quantity of fuel is made by enzymes, biological catalysts fine-tuned over aeons to extract every last joule of usable energy from reactions.

The enzymes that powered the first life cannot have been as efficient, and the first cells must have needed a lot more energy to grow and divide – probably thousands or millions of times as much energy as modern cells. The same must be true throughout the universe.

This phenomenal energy requirement is often left out of considerations of life’s origin. What could the primordial energy source have been here on Earth? Old ideas of lightning or ultraviolet radiation just don’t pass muster. Aside from the fact that no living cells obtain their energy this way, there is nothing to focus the energy in one place. The first life could not go looking for energy, so it must have arisen where energy was plentiful.

Today, most life ultimately gets its energy from the sun, but photosynthesis is complex and probably didn’t power the first life. So what did? Reconstructing the history of life by comparing the genomes of simple cells is fraught with problems. Nevertheless, such studies all point in the same direction. The earliest cells seem to have gained their energy and carbon from the gases hydrogen and carbon dioxide. The reaction of H2 with CO2 produces organic molecules directly, and releases energy. That is important, because it is not enough to form simple molecules: it takes buckets of energy to join them up into the long chains that are the building blocks of life.

A second clue to how the first life got its energy comes from the energy-harvesting mechanism found in all known life forms. This mechanism was so unexpected that there were two decades of heated altercations after it was proposed by British biochemist Peter Mitchell in 1961.

Universal force field

Mitchell suggested that cells are powered not by chemical reactions, but by a kind of electricity, specifically by a difference in the concentration of protons (the charged nuclei of hydrogen atoms) across a membrane. Because protons have a positive charge, the concentration difference produces an electrical potential difference between the two sides of the membrane of about 150 millivolts. It might not sound like much, but because it operates over only 5 millionths of a millimetre, the field strength over that tiny distance is enormous, around 30 million volts per metre. That’s equivalent to a bolt of lightning.

Mitchell called this electrical driving force the proton-motive force. It sounds like a term from Star Wars, and that’s not inappropriate. Essentially, all cells are powered by a force field as universal to life on Earth as the genetic code. This tremendous electrical potential can be tapped directly, to drive the motion of flagella, for instance, or harnessed to make the energy-rich fuel ATP.

However, the way in which this force field is generated and tapped is extremely complex. The enzyme that makes ATP is a rotating motor powered by the inward flow of protons. Another protein that helps to generate the membrane potential, NADH dehydrogenase, is like a steam engine, with a moving piston for pumping out protons. These amazing nanoscopic machines must be the product of prolonged natural selection. They could not have powered life from the beginning, which leaves us with a paradox.

[div class=attrib]Read the entire article following the jump.[end-div]

[div class=attrib]Image: Transmission electron microscope image of a thin section cut through an area of mammalian lung tissue. The high magnification image shows a mitochondria. Courtesy of Wikipedia.[end-div]