Rapamycin extends life in mice through mechanisms similar to those of calorie restriction, but has serious side-effects - though researchers are working to separate the positive mechanisms from the undesirable negative mechanisms. Metformin is also thought to be a calorie restriction mimetic drug, but the evidence for it to extend life in mice is mixed. Here, researchers suggest trying both drugs at the same time in the hopes that metformin blunts some of the side-effects of rapamycin: "Treatment with rapamycin, an inhibitor of mammalian target of rapamycin complex 1 (mTORC1) can increase mammalian life span. However, extended treatment with rapamycin results in increased hepatic gluconeogenesis concomitant with glucose and insulin insensitivity through inhibition of mTOR complex 2 (C2). Genetic studies show that increased life span associated with mTORC1 inhibition can be at least partially decoupled from increased gluconeogenesis associated with mTORC2 inhibition. Adenosine monophosphate kinase (AMPK) agonists such as metformin, which inhibits gluconeogenesis, [might] be expected to block the glucose dysmetabolism mediated by rapamycin."

Link: http://dx.doi.org/10.1089/rej.2012.1347

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

T-cell vaccines are a comparatively new approach to steering the immune system to perform tasks normally left undone, such as clearing out persistent herpesviruses. It is a reminder that the heading of immune therapy covers a very wide range of possible technologies, not all of which are even on the drawing board yet, and it will be an important part of the longevity science toolkit in the years to come.

An introduction to T-cell vaccine research can be found at the Technology Review:

All existing vaccines rouse the body into creating antibodies that attach to the surface of infecting microbes and flag them for destruction. But pathogens that live inside our cells, such as the viruses, bacteria, and other microbes that cause AIDS, malaria, herpes, and chlamydia, can evade this surveillance. ... In order to deal with those types of pathogens, oftentimes we have to stimulate what we call cellular immunity. Unlike antibody immunity, which recognizes pathogens directly, cellular immunity has to recognize the infected cell and get rid of your own infected cells.

But activating cellular immunity - and the family of infection-fighting cells known as T cells that drive it - is challenging. The trial-and-error method used to develop antibody-based vaccines has not worked for T-cell vaccines. Despite years of academic and industry work, and even clinical trials, there are no T-cell vaccines for infectious disease on the market.

...

A Cambridge, Massachusetts, biotech company called Genocea thinks its high-throughput method could change that. The company will begin its first clinical trial later this year, when its experimental herpes vaccine will be the first test of its claims.

The first and most straightforward way in which a working T-cell vaccine platform might be used to extend life expectancy is as a therapy to clear out the common herpesvirus known as cytomegalovirus (CMV). Most of the population carries strains of CMV by the time they reach old age, and it is thought that CMV plays a role in progressive immune system disarray:

Most people are exposed to this mild persistent herpesvirus over the course of their life; it causes few obvious symptoms, but over time more and more of your immune system resources become uselessly specialized to fight it. An immune cell dedicated to remembering the signature of CMV is unavailable for other uses - and eventually you run out of cells to protect you from new threats, destroy cancers, and clear out senescent cells. This process is one part of the frailty and increased risk of death and disease that comes with old age.

But there are other many other potential uses as well. A more mature T-cell vaccine platform could lead to an array of targeted cell destruction therapies. Destroying cells is, after all, one of the tasks that immune cells have evolved to carry out. A way of rapidly generating new, reliable, and selective methods to destroy very specific cell populations will be helpful in a very wide range of therapies designed to hold back the depredations of aging. For example, such a therapy might be used to cull the unwanted cells that clog up the immune system and degrade its effectiveness - including the memory cells uselessly devoted to persistent CMV strains.

Equally there are cancer cells, senescent cells (if researchers can figure out a better way of reliably identifying them from their surface chemistry), and all sorts of other cells we'd be better off without. Destroying them will repair some of the harms of aging caused by their presence. The most cost-effective way to get rid of them all is via some form of versatile technology that can be quickly adapted to new targets - and it's a fair bet that the first forms of that technology will involve learning how to manipulate the immune system to get the job done. Why reinvent the wheel when you can use what already exists?

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

It is known that calorie restriction increases stem cell capacity in aging, thereby helping to maintain tissues for longer. From Extreme Longevity, a recent commentary on the mechanisms involved: "Like it or not food lovers, the single most effective known means of extending animal lifespan is through reducing daily caloric intake. Though not definitively proven in humans, the success of this intervention has been demonstrated in myriad species in more than 50 years of research. ... A protein called mTOR is responsible for this effect. mTOR combines with two other proteins to mediate several important cellular processes. These include translation of mRNA into protein, mitochondrial activity, and autophagy. Caloric restriction inhibits mTOR activity which leads to longer lifespan. The new studies [convincingly] demonstrate that reduction of mTOR activity causes preservation of stem cell health. They increase in abundance and proliferative potential. One study shows this occurs in intestinal cells, and the other in muscle cells. In the instestinal cell study, the authors showed that it was actually supporter cells called Paneth cells that aided the health of stem cells when they were taken from calorie restricted animals. They further showed this effect was mediated by mTOR inhibition and that it was achieved by increasing the activity of another protein called Bst1, important in cell proliferation. In the muscle study, calorie restricted animals had greater muscle stem cell proliferative capacity too. And this effect was also seen when the stem cells were transplanted into non calorically restricted animals, suggesting the microenvironment or niche around the stem cells was key. ... taken together, the two studies indicate that preserving and enhancing stem-cell function in multiple tissues is one of the ways in which calorie restriction slows the ravages of aging."

Link: http://extremelongevity.net/2012/06/29/caloric-restriction-extends-lifespan-by-increasing-stem-cell-function/

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

An open access commentary: "The mammalian heart must maintain its structural and functional integrity for decades, yet the response to damage in this vital organ is remarkably inadequate and often results in heart failure. Moreover, patients with chronic heart failure show profound metabolic changes, leading to peripheral abnormalities in addition to an initial cardiac impairment. Several evidences have suggested a relationship between the IGF-1 system and cardiovascular disease. Many cardiovascular risk factors, such as sedentary lifestyle, diabetes, smoking, oxidized low-density lipoprotein, obesity, psychological distress and reduced coronary flow reserve, have been associated with reduced IGF-1 levels. Conversely, human studies indicate that increased levels of IGF-1 are characterized by a decreased incidence of heart failure and mortality in elderly individuals. Nevertheless, the fact that IGF-1 can act either as a circulating hormone or as a local growth factor has confounded previous analyses of animal models in which transgenic IGF synthesized in extra-hepatic tissues was released into the circulation. Locally acting mIGF-1 isoform improves muscle regeneration and counters muscle wasting associated with diseases, including sarcopenia, muscular dystrophy and ALS. By contrast, circulating IGF-1 isoforms have been implicated in the restriction of lifespan and have contrasting effects on the heart when expressed as transgenes, variously promoting cell survival, or inducing prolonged hypertrophy with pathological consequences."

Link: http://www.impactaging.com/papers/v4/n6/full/100466.html

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

If more life science researchers thought like engineers, we might see faster progress towards extended healthy longevity. One of the marks of pure engineering versus pure science is the willingness to pursue development of working solutions in the absence of full knowledge of the underlying principles. Both the Romans and the early British industrialists built superb bridges in the absence of a full understanding of structural and material science, not by chance but because they could deliberately and carefully use empirical knowledge to work around their ignorance of deeper scientific laws. So too there is much more room for empiricism in the development of medicine, and in longevity science in particular, than is presently practiced. In the scientific world, the favored next step following a demonstration of extended life in laboratory animals is to figure out every detail of how it works rather than explore the possibility of building a therapy - but both paths could be explored in parallel.

In any case, here are results from a group of life science engineers, working with nematode worms:

We have taken an engineering approach to extending the lifespan of Caenorhabditis elegans. Aging stands out as a complex trait, because events that occur in old animals are not under strong natural selection. As a result, lifespan can be lengthened rationally using bioengineering to modulate gene expression or to add [components from other species].

...

We overexpressed five genes that act in endogenous worm aging pathways, as well as two genes from zebrafish encoding molecular functions not normally present in worms. For example, we used zebrafish genes to alter mitochondrial function and innate immunity in ways not normally available to C. elegans and extended worm lifespan by ~40%. Next, we used a modular approach to extend lifespan by 130% by combining up to four components in the same strain. These results provide a platform to build worms having progressively longer lifespans.

This project is conceptually similar to using engineering to increase the useful lifespan of a primitive machine (1931 Model T) using both parts from the model T as well as parts from a more advanced machine (2012 Toyota Corolla). Our results open the door to use engineering to go beyond the constraints of the C. elegans genome to extend its lifespan by adding non-native components.

Tinkering with metabolism and genes to slow aging isn't my favored approach for extending healthy longevity - it is a poor path in comparison to efforts aimed at repairing accumulated damage - but I am very much in support of the attitude displayed by the authors quoted above. The research community could do with a whole lot more of that sort of mindset.

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