Longevity Meme Newsletter, August 17 2009

August 17 2009

The Longevity Meme Newsletter is a weekly e-mail containing news, opinions, and happenings for people interested in healthy life extension: making use of diet, lifestyle choices, technology, and proven medical advances to live healthy, longer lives.



- On Skin Photoaging
- Aubrey de Grey and S. Jay Olshansky to Debate
- Cancer Stem Cell Theory Continues to Look Promising
- Discussion
- Latest Healthy Life Extension Headlines


Research into the (somewhat) accelerated aging of skin through exposure to UV light bears some resemblance to aging research in general, and some resemblance to research into accelerated aging conditions like progeria:


"Researchers are largely on the same page when it comes to how aged skin is different from young skin - questions revolve around the processes that lead to that point. As for aging research in general, you can see camps in any sub-field - such as skin aging here - emerge and center around known areas of interest such as mitochondrial damage, telomere shorting, or nuclear DNA damage.

"As in other parts of aging research, no great resolution has been reached as to how much each of these processes contribute to overall degeneration, and which processes might be cause or effect of other processes. All sides have indirect evidence to point to in support of their position, so this might continue for another decade before an evidence-backed consensus emerges."


Longevity science advocates Aubrey de Grey and S. Jay Olshansky will present their respective viewpoints at a September conference on life expectancy and actuarial risk. The conference - and debate - is aimed at those who invest vast sums of money into the longevity insurance and life insurance marketplace, such as hedge fund managers:


"Insofar as anyone gets to be appointed spokesperson, de Grey and Olshansky might be considered spokespeople for the two opposing viewpoints on research strategy in the pro-longevity gerontology community today. On the one hand we have the Strategies for Engineered Negligible Senescence that focus on repair of damage and circumventing incomplete understanding of our biochemistry, with the goal of reversing aging and rejuvenating the old as soon as possible. On the other hand, we have the Longevity Dividend and metabolic engineering, efforts with a focus on establishing complete understanding of our biochemistry and using that understanding to slow down the ongoing progression of aging.

"Note that there are ever fewer voices from the scientific community arguing that we should not or cannot significantly intervene in the aging process. The consensus is that we can, and the important debates are all now over methodology and timelines."


Cancer stem cell theory states that cancers are supported in their growth by a small and distinct population of errant stem cells. Remove the stem cells, such as with the next generation of targeted immune therapies or nanotechnology-based therapies, and the cancer will die:


"A vigorous scientific debate is presently underway. Are cancer stem cells damaged versions of normal stem cells, and do they exist in all cancers? Or are there characteristic ways in which normal cells become reprogrammed into cancer stem cells? After all, induced pluripotent stem cells show that normal cells can be altered in just a few ways to give them the characteristics of embryonic stem cells - such as unchecked growth. Or is it the case that cancers, mutating rapidly, will generate a huge variety of stem-like cells to support their growth, and thus there are few if any commonalities to target?

"All of these points of view presently have some experimental results to back them up. New results continue to be published at a pace that suggests it won't be too many more years before the contradictions are reconciled and the important question answered: are cancer stem cells a short cut to killing most or all cancers? At present it looks plausible that the answer is yes."


The highlights and headlines from the past week follow below.

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This open access paper contains an interesting discussion of genetic investigations in the oldest of people who manage to avoid age-related disease and stay comparatively healthy: "Individuals who live to 85 and beyond without developing major age-related diseases may achieve this, in part, by lacking disease susceptibility factors, or by possessing resistance factors that enhance their ability to avoid disease and prolong lifespan. ... Besides genes that have been shown to affect lifespan in animal models, a limited number of genetic variants have been reported to be associated with long life in humans. These studies mainly evaluated genetic variation linked to extreme human life spans (e.g. centenarians) without focusing specifically on health. ... Controversy exists regarding the contribution of these and other gene variants to aging and longevity, because replication studies in different populations, as for replication studies in complex diseases, more often than not fail to confirm the initially reported associations. ... Healthy aging is a complex phenotype likely to be affected by both genetic and environmental factors. We sequenced 24 candidate healthy aging genes in DNA samples from 47 healthy individuals aged eighty-five years or older (the 'oldest-old'), to characterize genetic variation that is present in this exceptional group. These healthy seniors were never diagnosed with cancer, cardiovascular disease, pulmonary disease, diabetes, or Alzheimer disease."

A reminder that the Aging and Healthy Lifespan Conference will be held on September 23rd - next month - at Harvard Medical School. "Over the next 20 years, the population of Americans over age 65 is expected to double, and health care spending is projected to increase by 25%. With an aging society, it is crucial to understand the challenges and address the opportunities to target diseases of aging, such as cancer and type 2 diabetes, to allow people to live longer, healthier lives. ... Hear leading experts discuss emerging research into scientific and medical advances in aging, as well as lifestyle and demographic trends. This first-ever conference will feature two speaker tracks. One track will focus on new research and insights in the science of aging including updates on the exciting science behind sirtuins and resveratrol. The second track will feature emerging social trends in lifestyles, behaviors and activities of the aging population." Note that longevity science advocate Aubrey de Grey and a number of speakers from the Calorie Restriction Society will be there, alongside researchers whose names I'm sure you'll recognize.

Cancer mortality rates have declined for decades now, a trend that we should expect to see continue and accelerate given the technology demonstrations emerging from the laboratories: "Our efforts against cancer, including prevention, early detection and better treatment, have resulted in profound gains, but these gains are often unappreciated by the public due to the way the data are usually reported ... Cancer mortality rates are usually reported as composite age-adjusted rates. These rates have been declining modestly since the 1990's. However, these statistics heavily emphasize the experience of the oldest Americans for whom mortality rates are the highest. As a result, trends emerging in younger Americans can be concealed. As an alternative to age-adjustment, Kort examined cancer mortality rates stratified by age and found that for individuals born since 1925, every age group has experienced a decline in cancer mortality. The youngest age groups have experienced the steepest decline at 25.9 percent per decade, but even the oldest groups have experienced a 6.8 percent per decade decline."

Here biomedical gerontologist Aubrey de Grey defines "regenerative medicine" somewhat more broadly than just stem cell therapies and enhanced healing: "The human body is, ultimately, a machine - an astronomically complex machine, of whose workings we remain pitifully ignorant - but still a machine. Like any machine, it accumulates 'damage' as a side-effect of its normal operation: molecular and cellular changes that occur throughout life are initially harmless, but eventually (when too abundant) increasingly impede the normal operation of the machine and eventually cause it to fail altogether. ... The relevance of nearly all biogerontology research to combating aging is restricted to the potential for slowing down the accumulation of molecular and cellular damage that eventually leads to age-related ill-health. Meanwhile, regenerative medicine has been progressing rapidly and is nearing clinical applicability to a wide range of specific conditions. My view is that we are approaching the point where regenerative medicine can be used against aging. This would entail not retarding but actually reversing the accumulation of damage. If successful, this would obviously be a far more valuable technology than mere slowing of aging. However, in order to be successful it must be comprehensive, and some aspects of aging may seem impossible to address in this way. In fact, however, it seems that all types of molecular and cellular damage which contribute to age-related ill-health are realistic targets of regenerative interventions."

FuturePundit looks at one of a number of studies showing calorie restriction to reduce the risk of cancer: "Previous studies have shown that intermittent calorie restriction provided greater protection from mammary tumor development than did the same overall degree of restriction, which was implemented in a chronic fashion. The researchers compared changes of a growth factor (IGF-1) in relationship to these two calorie restriction methods - chronic and intermittent - and tumor development beginning in 10-week old female mice at risk to develop mammary tumors. Their hope was to explain why intermittent restriction is more effective. The overall degree of restriction was 25 percent reduction compared to control mice. Mammary tumor incidence was 71 percent in the control mice who ate the amount of food they wanted, 35 percent among those who were chronically restricted and only nine percent in those who intermittently restricted calories." Which is further evidence for those who suspect that intermittent fasting operates through different biochemical mechanisms to calorie restriction, despite a similar outcome in terms of extended health and longevity.

The widespread veterinary use of stem cell therapies in past years well demonstrates that there is no good reason for regulatory barriers blocking human application of these technologies: "Vet-Stem, a Poway, Calif.-based company, is developing the stem cell therapy and began treating horses in 2003. It derives stem cells from fat samples taken from dogs and horses across the country. The procedure has been used mainly to treat osteoarthritis, which involves loss of cartilage in the joints, but Vet-Stem is researching treatments for other diseases. Vet-Stem claims the therapy enables animals to replace cartilage and other tissue. Since 2003, the privately held company has treated 3,500 horses and 1,500 dogs and plans to begin treating cats later this year. More than 1,500 vets are licensed to use the procedure. ... Really, all we're doing is harnessing the existing repair machinery in the body, concentrating it, and putting it right where an injury occurs, where healing is needed, to heal naturally. ... One peer-reviewed [study] sponsored in part by Vet-Stem, found that tendinitis in horses was improved by injection of the adult stem cells. Two other studies published in Veterinary Therapeutics found that dogs with osteoarthritis showed improvements in lameness after stem cell injections. Those studies also were sponsored by Vet-Stem and conducted by Vet-Stem researchers and other veterinarians."

This research group proposes that Sirt3 acts on longevity through increasing antioxidants - we should all be appropriately skeptical, given the very mixed evidence for links between cellular antioxidants and longevity. That said, Sirt3 is located in the mitochondria, and the demonstrations of extended life spans through increased antioxidants have involved targeting those antioxidants to the mitochondria. "Sirtuin 3 (SIRT3) is a member of the sirtuin family of proteins that promote longevity in many organisms. Increased expression of SIRT3 has been linked to an extended life span in humans. ... Of the 7 SIRT analogues, SIRT3 is the only member whose increased expression has been linked to the longevity of humans. Polymorphism in the SIRT3 gene promoter, which leads to gene activation, has been found to be associated with an extended life span of man. The molecular basis of SIRT3-dependent longevity is, however, not known. ... In primary cultures of cardiomyocytes, Sirt3 blocked cardiac hypertrophy by activating the forkhead box O3a–dependent (Foxo3a-dependent), antioxidant–encoding genes manganese superoxide dismutase (MnSOD) and catalase (Cat), thereby decreasing cellular levels of ROS. ... These results demonstrate that SIRT3 [protects] hearts by suppressing cellular levels of ROS."

Creating patient specific blood cells will enable many, many applications - especially in an era of immune therapies. Even the simple ability to greatly multiply the number of white blood cells in a patient's body for a short while can be profoundly beneficial. Here is an update on progress towards engineered blood cells made to order: "In an advance that could help transform embryonic stem cells into a multipurpose medical tool, [scientists] have transformed these versatile cells into progenitors of white blood cells and into six types of mature white blood and immune cells. While clinical use is some years away, the new technique could produce cells with enormous potential for studying the development and treatment of disease. The technique works equally well with stem cells grown from an embryo and with adult pluripotent stem cells, which are derived from adult cells that have been converted until they resemble embryonic stem cells. If the adult cells came from people with certain bone marrow diseases, the new technique could produce blood cells with specific defects. It could also be used to grow specific varieties of immune cells that could target specific infections or tumors."

As researchers continue to discover and manipulate the mechanisms of cell programming, the new knowledge generated will impact many other fields of medicine: "research links cancer development with difficulties in the new technology of reprogramming normal cells into becoming like embryonic stem cells ... Nearly all cancers have a disabled p53 gene. The gene causes cells that have experienced major genetic damage, which puts them at high risk of turning malignant, to self-destruct. While several mutated genes are implicated in cancer, p53 appears to be the most important one. ... When the p53 gene is removed, normal cells can be reprogrammed into stem cells with a tenfold greater success rate ... If the link is confirmed by other researchers, it would undermine a popular hypothesis that cancers arise from 'cancer stem cells,' caused by genetic changes in stem cells. [Instead] cancer could begin when normal cells spontaneously reprogram themselves, for reasons yet unknown, beginning the process that results in a cancerous tumor. ... A better understanding of how to cause reprogramming could provide clues about how this might arise spontaneously. And that knowledge could be useful in developing cancer-fighting therapies."

More interesting cancer stem cell research: "researchers report that the STAT3 gene regulates cancer stem cells in brain cancer. Cancer stem cells have many characteristics of stem cells and are thought to be the cells that drive tumor formation. The researchers report that STAT3 could become a target for cancer therapy, specifically in Glioblastoma multiforme (GBM), a type of malignant and aggressive brain tumor. ... STAT3 has been shown to be activated in a number of human tumors. This study is one of the first to show, however, that STAT3 regulates cancer stem cells. It is one of the few genes linked to the propagation of cancer stem cells, and it appears to regulate processes involved in the six hallmarks of cancer: growth, metastasis, angiogenesis, evasion of apoptosis, tissue invasion, and cell immortalization. ... Current cancer therapies that prolong life do not specifically target cancer stem cells, and these cells are often resistant to traditional radiation and chemotherapies. ... When STAT3 is inhibited, cancer stem cells in glioblastomas lose their stem-cell characteristics permanently, suggesting that STAT3 regulates growth and self-renewal of stem cells within glioblastomas. Strikingly, a single, acute treatment with STAT3 inhibitors was effective, implying that a STAT3 inhibitor could stop tumor formation."



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