Over at the SENS Foundation, you'll find fairly detailed commentary from Michael Rae on the recent news of progress towards a viable therapy for the rare accelerated aging condition progeria. As I've noted in recent years, one of the things learned about the mechanisms of progeria is that they seem to be a greatly exaggerated version of processes that happen in all of us - in the same sense that the runaway mechanisms of Alzheimer's or Parkinson's disease (and many other age-related conditions) take place at low levels in all of us.

So should we do more than keep a weather eye on progeria research? Probably not:

All of us at SENS Research Foundation are inspired by the rapid progress that was made against this tragic disease ... However, it is also important not to read too much into this apparent advance in regards to its implications for the development of new medicines against the diseases and disabilities of aging. In particular, the common characterization of HGPS "progeria" as a disease of "premature aging" leads some to expect that this research has direct implications for the development of rejuvenation biotechnologies, targeting the damage and disabilities of aging.

It is true that the splicing defect responsible for formation of progerin is sporadically active in wild-type cells, and that number of cells in which progerin is present and the level at which it appears do appear to rise with aging. However, such cells are rare enough, and their progerin levels low enough, as to seem highly unlikely to meaningfully contribute to tissue dysfunction with aging, at least within the bounds of a currently-normal lifespan. Additionally, there is evidence that progerin can be turned over in the nuclear lamina, and the causal relationship between the higher prevalence of progerin in aging cells and cellular senescence or disease are not clear, leaving open the possiblity that repair of well-established forms of aging damage may in turn lead to the reversal or obviation of this phenomenon.

Notably, the need to remove "senescent" cells as part of a comprehensive panel of rejuvenation biotechnologies is already clear from first principles, and its potential to ameliorate aspects the frailty and disability of aging has been demonstrated in proof-of-concept rejuvenation research, rendering the specific role of progerin in the process moot. That is, removing "senescent" cells is essential whether progerin accumulation is a cause or a consequence of cellular senescence, and will be equally effective as a regenerative medical therapy against age-related disability in either case.

It is absolutely the case that we'd expect new and interesting challenges to show up once people are living well past the normal human life span. We'd expect to see forms of biological damage that are generally irrelevant over the course of a century turn out to be lethal at two centuries, for example - perhaps nuclear DNA damage, perhaps progerin accumulation, perhaps the fact that some important macromolecules are never normally replaced, perhaps more obscure aggregated metabolic waste products. So largely things we presently know about, can presently ignore, and will have a great deal of time to work on should it turn out to be problem down the line.

Source:
http://www.longevitymeme.org/newsletter/latest_rss_feed.cfm

It is thought that size in humans relates to life expectancy via aspects of metabolism such as growth hormone - less growth hormone means a smaller size but longer life in mammal species. Ames dwarf mice are an example of this taken to an extreme through genetic engineering, lacking growth hormone but living more than 60% longer than their peers.

From an evolutionary perspective, an abundance of food and good health in early life or gestation is thought to trigger a more aggressive front-loading of growth and fertility - which comes at the cost of faster decline once an individual is beyond their reproductive lifespan:

Sardinians have been studied extensively looking for clue to long lifespan. In the current study researchers analyzed the role of a person's height in their eventual lifespan. The researchers analyzed the height of men when they entered the military at age 20 between the years of 1866 and 1915. A total of 685 subjects were analysed. These heights were then related to the persons eventual age at death. It was found that shorter people (shorter than 161.1 cm) lived significantly longer on average than taller people (taller 161.1cm). Furthermore at age 70, taller people lived on average 2 years less than shorter people. At age 70 each quarter inch of height reduced lifespan by one year.

The authors write: In conclusion, shorter people and taller people exhibit differences in longevity. Although a tall body generally reflects abundant nutrition and good living conditions during the growth period, this height has negative ramifications as well. Biological mechanisms indicate that a larger body places greater stress on cells, tissues, and organs, which can reduce longevity.

Link: http://extremelongevity.net/2012/09/26/shorter-people-live-longer/

Source:
http://www.longevitymeme.org/newsletter/latest_rss_feed.cfm

Telomeres are the protective caps at the end of chromosomes. They shorten with cell division, and so are part of the clock which decides when a cell reaches the Hayflick limit and ceases dividing. There is much more to it than this, however: telomere length across all the cells in a piece of living tissue is dynamic, as there are processes that lengthen telomeres as well - such as the activity of telomerase.

In general average telomere length erodes with age, reflecting the progressive breakdown of the body's ability to maintain itself - but this proceeds quite differently in different tissues and different species. It can even be reversed in the short term if the health of an individual improves, though in the long term the overall progression is still downhill.

Shorter average telomere length has been correlated with measures of health in statistical studies, but data allowing prediction of longevity for an individual has proven elusive to date. Here, however, a more sophisticated measure of telomere dynamics is show to be predictive of life span in individual mice:

Aberrantly short telomeres result in decreased longevity in both humans and mice with defective telomere maintenance. Normal populations of humans and mice present high interindividual variation in telomere length, but it is unknown whether this is associated with their lifespan potential. To address this issue, we performed a longitudinal telomere length study along the lifespan of wild-type and transgenic telomerase reverse transcriptase mice.

We found that mouse telomeres shorten ?100 times faster than human telomeres. Importantly, the rate of increase in the percentage of short telomeres, rather than the rate of telomere shortening per month, was a significant predictor of lifespan in both mouse cohorts, and those individuals who showed a higher rate of increase in the percentage of short telomeres were also the ones with a shorter lifespan. These findings demonstrate that short telomeres have a direct impact on longevity in mammals, and they highlight the importance of performing longitudinal telomere studies to predict longevity.

Link: http://dx.doi.org/10.1016/j.celrep.2012.08.023

Source:
http://www.longevitymeme.org/newsletter/latest_rss_feed.cfm

Based on what we know today, inhibition of myostatin in muscle tissue looks like one of the few win-win, all-round beneficial alterations that could be made to human metabolism. Lacking myostatin, a mutation that occurs naturally in very rare cases, an individual has much more muscle, less fat, and resistance to some of the common issues that occur with aging - though it is unclear as to how much of that latter benefit stems from an extended ability to exercise and the comparative lack of visceral fat. A sedentary lifestyle and excess visceral fat are both very bad for you over the long term, causing a shorter life expectancy and greater risk of many forms of age-related disease and disability.

Myostatin inhibitors are under investigation as the potential basis for therapies to slow or reverse the progressive loss of muscle mass and strength that occurs with age, a condition known as sarcopenia. The physical frailty of aging is something of a self-reinforcing downward spiral, and addressing even just the muscle strength component of this decline could bring noteworthy benefits.

Research into myostatin dovetails with research into the decline of stem cells with aging, such as the satellite cells in muscle. The fading activity of the satellite stem cell populations that support muscle tissue is thought to be one contributing cause of sarcopenia. Others range from chronic inflammation through to a progressive inability to make proper use of leucine in the diet.

There is no claim that inhibition of myostatin will address the root causes of sarcopenia: it is more a matter of dialing up the "build muscle" switch to levels that do not normally occur as a way of compensation. As a method of doing so it seems to cause no undue complications - which is a good thing and sadly very rare due to the overwhelming complexity of our biology - but it is nonethless far from ideal. In that ideal world, we'd want all therapies (for aging or otherwise) to tackle root causes rather that patch over symptoms, but sometimes you take what you can get.

In any case, here is an update from the world of myostatin research with some additional information on how things tie together under the hood:

Blocking myostatin function in normal mice causes them to bulk up by 25 to 50 percent. What is not known is which cells receive and react to the myostatin signal. Current suspects include satellite cells and muscle cells themselves. In this latest study, researchers used three approaches to figure out whether satellite cells are required for myostatin activity. They first looked at specially bred mice with severe defects in either satellite cell function or number. When they used drugs or genetic engineering to block myostatin function in both types of mice, muscle mass still increased significantly compared to that seen in mice with normal satellite cell function, suggesting that myostatin is able to act, at least partially, without full satellite cell function.

...

to further confirm their theory that myostatin acts primarily through muscle cells and not satellite cells, the team engineered mice with muscle cells lacking a protein receptor that binds to myostatin. If satellite cells harbor most of the myostatin receptors, removal of receptors in muscle cells should not alter myostatin activity, and should result in muscles of normal girth. Instead, what the researchers saw was a moderate, but statistically significant, increase in muscle mass. The evidence once again, they said, suggested that muscle cells are themselves important receivers of myostatin signals. ... since the results give no evidence that satellite cells are of primary importance to the myostatin pathway, even patients with low muscle mass due to compromised satellite cell function may be able to rebuild some of their muscle tone through drug therapy that blocks myostatin activity.

"Everybody loses muscle mass as they age, and the most popular explanation is that this occurs as a result of satellite cell loss. If you block the myostatin pathway, can you increase muscle mass, mobility and independence for our aging population? [Our] results in mice suggest that, indeed, this strategy may be a way to get around the satellite cell problem."

So myostatin inhibition continues to look like a promising form of patch, in that it fails to address root causes but nonetheless produces meaningful benefits with few if any unwanted side-effects - which is more than can be said for many other forms of patch either in operation or under development in the world of medicine.

Source:
http://www.longevitymeme.org/newsletter/latest_rss_feed.cfm