Rejuvenation Research Volume 9 Number 3 is out and available online, in case you hadn't noticed. While, as usual, more than I note is there for your perusal, the following items caught my eye:
Given the constitutive expression of telomerase in the majority of human tumors, telomerase inhibition is an attractive, broad-spectrum therapeutic target for cancer treatment. Therapeutic strategies for inhibiting telomerase activity have included both targeting components of telomerase (the protein component, TERT, or the RNA component, TERC) or by directly targeting telomere DNA structures. Recently a combination telomerase inhibition therapy has been studied also. ... The 10% to 15% of immortalized cancer cells that do not express telomerase use a recombination based mechanism for maintaining telomere structures that has been called the alternative lengthening of telomeres (ALT). In view of the increasing study of telomerase inhibitors as anticancer treatments, it will be crucial to determine whether inhibition of telomerase will select for cancer cells that activate ALT mechanisms of telomere maintenance.
It seems clear that much can be done with a better understanding of the cellular mechanisms hijacked and redirected by cancer. Cancer is, in essence and skipping over most of the important subtleties, a failure of the body's turnover mechanism for cells - it is suddenly immortal cells run amok. At the more ambitious end of the pool, we have proposals like Aubrey de Grey's Whole-body Interdiction of Lengthening of Telomeres, a part of the Strategies for Engineered Negligible Senescence (SENS). Considering near term goals, however, a number of research groups and young companies are hacking away at the undergrowth to find the best gains to be made in the short term.
Reduction of oxidative stress within mitochondria is a major focus and important part in the SENS agenda. The age-related accumulation of mitochondria rich in oxidatively altered DNA may be a biomarker of malfunctioning and increased oxidative stress. Macroautophagy is the cell repair mechanism responsible for the disposal of excess or altered mitochondria under the inhibitory control of nutrition and insulin, and may mediate the antiaging effects of caloric restriction. ... It is concluded that the age-related changes in [mitochondrial DNA (mtDNA)] and function are likely to be the consequence of a failure of macroautophagy in the recognition and disposal of a small number of severely injured mitochondria, and that easy and safe ways are available to counteract this change.
I am very pleased to see more researchers taking SENS as a challenge, or goal list. This sort of mindset will go a long way towards bringing people on board and putting accomplishments on the table. More to the point, and like the protofection folk, this group is demonstrating some tangible results - albeit not so far advanced and not in vivo.
Werner syndrome (WS) is a premature aging disorder that is widely used as a model for some aspects of the normal human aging process. Individuals with WS have several of the characteristics of normal aging, such as cataracts, hair graying, and skin aging, but manifest these at an early age. In addition, WS is associated with high levels of inflammatory diseases such as atherosclerosis and type II diabetes. Recent data have indicated that fibroblasts derived from individuals with WS have activated a major molecular pathway involved in inflammation. This observation ties in with the presence of high plasma levels of inflammatory cytokines in individuals with WS. In this paper, the authors discuss the possibility that WS is an example of "inflamm-aging," in that many of the phenotypic manifestations may result from an increased inflammatory state. Moreover, drugs that specifically block this inflammation pathway may be possible candidates for therapeutic intervention in WS.
Inflammaging is a great term - very catchy, to the point and representative of exactly what it is that chronic inflammation does to you. We need more of these catchy terms as we go forward in our attempts to bring an understanding of healthy life extension to a wider audience (starting with a replacement for "healthy life extension" and "anti-aging").
But back to the research at hand. This caught my eye precisely because scientists have recently nailed down progeria - another accelerated aging condition - to be the result of a biochemical process seen in "normal" aging that is exaggerated out of all proportion due to a single genetic mutation. The aging process is very multifaceted for most of us, but progeria is a case of one - apparently comparatively minor - facet racing ahead of all others to dominate and shorten life span.
Present indications are that Werner syndrome is a matter of failing DNA repair mechanisms; thus its syndromes are a consequence of an increased rate at which unrepaired DNA damage accumulates. That isn't completely cut and dried, however; it will be interesting to see how inflammation fits into this. What is the cause and what is the consequence? Further research will show the answer, and the knowledge gained will most likely benefit wider longevity research - just as for progeria.