Longevity Meme Newsletter, September 13 2010

September 13 2010

The Longevity Meme Newsletter is a weekly email containing news, opinions, and happenings for people interested in aging science and engineered longevity: making use of diet, lifestyle choices, technology, and proven medical advances to live healthy, longer lives. This newsletter is published under the Creative Commons Attribution 3.0 license. In short, this means that you are encouraged to republish and rewrite it in any way you see fit, the only requirements being that you provide attribution and a link to the Longevity Meme.



- Atomic Medicine
- Why Are There No 400 Year Old Humans?
- Longevity-Associated Genes are No Longer Remarkable
- Discussion
- Latest Healthy Life Extension Headlines


The future of medicine, just like the future of manufacturing, will involve complex precision engineering at the level of atoms:


"We are collections of atoms, and the ills we suffer - aging included - are all, ultimately, caused by atoms being out of place. The medicines of today and all of history are nothing more than very crude and many-times-removed attempts to put errant atoms back where they belong. ... As Drexler and others have pointed out, to date we have worked with atoms only in bulk. We have shaped them with stones, pounded them with hammers, milled them by computer control. The manipulation of individual atoms, in a deft and dexterous fashion, would fulfill a contemporary definition of mastery over fabrication. The field of medicine also falls into the above category.

"Systems that can identify, manage and place trillions of molecules accurately are not a pipe dream; after all, we are already surrounded by examples. You, for example, are just such a system, albeit somewhat slow at self-assembly to full size. There's nothing in the laws of physics that jumps out and says we can't do this. It's just a matter of time. If you have the technology base to build a nanoforge to assemble a brick, then you also have the technology base capable of simultaneously assembling and controlling a hundred million medical nanorobots of arbitrary design and programming. Or an artifical lung better than the real thing, or replacements for immune cells that never get old or worn."


Small rodents in captivity routinely reach ten times their mean life span in the wild. Why is it then that in human populations with an average life span of 40 to 80 years nobody has ever lived to 400 years old or more?


"This is a fine and valid question. Why do we see little variation in human life span in comparison to that of smaller and more short-lived mammals? The authors of this paper performed an analysis of mortality statistics across different species of mammal, the results of which lead into a very interesting and readable discussion on the interaction between evolutionary pressures and age-related frailty. This is all part of the larger question of why we age, and why we age in the way we do."


Researchers are uncovering genes correlated with human longevity at an increasing rate - with the expectation that there may be thousands of genetic variants with significant correlations but small individual effects. For example:


"Estimates of the heritability of normal human lifespan range from 10% to 58%, averaging about 25%. The genetic contribution to lifespan grows markedly after age 60, indicating the heritability of exceptional longevity may be substantially higher than these estimates. The relative survival probability for siblings of centenarians increases steadily with age, until male and female siblings have a 17-fold and 8-fold increased chance, respectively, of reaching age 100 compared to others from their birth cohort. Moreover, while natural lifespan is likely a complex trait controlled by many genes with small effect sizes, extreme longevity may be determined by fewer genes of stronger effect.

"To map the [genetic] loci conferring a survival advantage, we performed the second genomewide linkage scan on human longevity and the first using a high-density marker panel of single nucleotide polymorphisms. By systematically testing a range of minimum age cutoffs in 279 families with multiple long-lived siblings, we identified [multiple longevity-associated loci]."


The highlights and headlines from the past week follow below.

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Recent research: "Aging has many different causes, says Jessica Tyler, a molecular biologist at the University of Texas MD Anderson Cancer Center in Houston. Now, Tyler and her colleagues think they have uncovered yet another way cells age - by losing histones. Histones are important proteins that form a spool upon which DNA is wound. This spooling allows yards of DNA to fit inside a cell and also helps control how genes are turned on and off. Tight winding helps keeps genes off, while loosening the packaging allows genes to be turned on. As yeast cells age they make fewer histone proteins, Tyler's team found. ... Exactly how histones determine how long yeast will live is still unknown. The researchers think falling levels of histones during aging may loosen DNA and allow many genes to be turned on inappropriately. That excess gene activity may zap a cell's energy reserves. Making extra histones may help old yeast keep tighter control of gene activity. ... the team found that the histone life-extension process is likely independent of other known mechanisms for increasing life-span. For instance, histones appear to work differently from the well-known antiaging sirtuin protein Sir2. ... Yeast on restricted-calorie diets live longer. So do yeast with more histones. If the two mechanisms are entirely independent of each other, combining the two treatments should add up to make yeast live longer than either manipulation alone. Instead, combining the treatments in the new experiments led to a life-span extension somewhere in between the solo effect of either treatment. The finding serves as a reminder that biological processes are complicated and intertwined."

OLDER AND HEALTHIER (September 10 2010)
From the Telegraph: "The negative effects of an aging population may have been exaggerated because people are staying healthier for longer, according to a new study. ... The two factors tend to balance each other out, the researchers found, suggesting that Governments may have overestimated the future costs of demographic changes. For instance, standard measures assume that over 65s are likely to need carers, whereas healthy elderly people are often themselves able to look after an even older relative, the report's authors said. ... If we apply new measures of aging that take into account increasing life-spans and declining disability rates, then many populations are aging slower compared to what is predicted using conventional measures based purely on chronological age. ... Their calculations show that in the United Kingdom, for example, while the old age dependency ratio is increasing, the disability ratio is remaining constant. What that means, according to the authors, is that [although] the British population is getting older, it is also likely to be getting healthier, and these two effects offset one another." Any "negative effects" of greater human longevity are entirely imaginary, or the product of broken regulatory systems that should be scrapped. Longer lives produced by modern medical technology are an unambiguously good thing.

Researchers uncover a potentially important lead: "Elimination of a molecular gatekeeper leads to the development of arthritis in mice ... The newly discovered gatekeeper is a protein that determines the fate - survival or death - of damaging cells that mistakenly attack the body's own tissues and lead to autoimmune disorders such as arthritis. ... An added bonus is that this finding may help in the search for new treatments for other autoimmune disorders, such as lupus. ... The protein at the center of the new finding, known as G alpha q, is part of a larger signaling pathway that Lund and collaborators from across the United States and China investigated in mice. G alpha q regulates B cells, one type of immune cell that the body maintains to fight off invaders like bacteria, viruses and parasites. While most B cells help defend the body, some B cells are autoreactive - they turn against the body's own tissues. ... Several new studies expanding on the current finding are in the works, including testing whether drug compounds that alter the expression or activity of G alpha q in mice can slow the development of autoimmunity. Beyond preclinical testing in mice, researchers also hope to start screening G alpha q levels in patients to learn more about how the protein works in humans."

This CNN article demonstrates the sort of willful persistence required to learn about and gain access to newer medical technologies that are not yet widely available: "The doctor who was on call at the emergency room told me there was no way he could reattach [the tip of] my pinky. I didn't like that, so I asked to see a specialist ... Eventually, Kulkarni made an appointment with Dr. Michael Peterson, an orthopedic surgeon in Davis. At first, [he] was hesitant to try tissue regeneration since he hadn't done it before, but she gave him some research materials, and she says eventually he agreed to try it.
The therapy involved cleaning out the finger and removing scar tissue - a process called debridement - and then dipping her finger into MatriStem wound powder. After seven weeks of treatment, her fingertip grew back. ... What I found out is that even though I like my doctors, I don't have to take every recommendation they give me. I can do my own research. ... Some doctors are more out-of-date or up-to-date than others. ... Imagine if I hadn't pursued other options because I was worried about what other people think - I didn't want to live with that regret." Fingertips are known to sometimes regenerate in very young children, but only in recent years has any methodology been shown to work in at least some adults.

Antagonistic pleiotropy is the tendency for a gene that is advantageous in youth to cause problems in later life - evolution selects for it despite the later cost. The trade-off between fertility and longevity might be thought of in this way, as the delayed cost of mechanisms that increase youthful fertility: "Aromatase (CYP19) and estrogen receptor-alpha (ESR1) are involved in the metabolism of estrogens, which have a relevant role in female and male aging. Moreover, due to their influence on fertility, both genes may be part of the longevity-fertility trade-off mechanism. This investigation examines the association of [ESR1 and CYP19 polymorphisms] with longevity. A sample of 258 individuals (mean age = 83.1 +/- 5.7 years) was recruited in 2000. Based on mortality data collected in 2009, the sample was divided into two groups of participants surviving more than 90 years or not. The analysis showed that ESR1 PP and CYP19 genotypes carrying the T allele were significantly associated with longevity (survival to age more than 90 years). As the ESR1 PP genotypes were found associated with reduced fertility in the same sample, we may infer that ESR1 genotypes could exert an antagonistic pleiotropic effect on longevity and fertility."

An open access paper on one of the causes of aging: "In neurodegenerative diseases, such as Alzheimer's disease and Huntington's disease, specific proteins escape the cell's quality-control system and associate together, forming insoluble aggregates. Until now, little was known about whether proteins aggregate in a non-disease context. In this study, we discovered that the aging process itself, in the absence of disease, leads to the insolubilization and increased aggregation propensity of several hundred proteins in the roundworm Caenorhabditis elegans. ... We asked if this inherent age-dependent protein aggregation impacts neurodegenerative diseases. We found that proteins similar to those aggregating in old worms have also been identified as minor components of human disease aggregates. In addition, we showed that higher levels of inherent protein aggregation aggravated toxicity in a C. elegans Huntington's disease model. Inherent protein aggregation is a new biomarker of aging. Understanding how to modulate it will lead to important insights into the mechanisms that underlie aging and protein aggregation diseases."

There will likely be a great many genetic contributions to human longevity, as this open access paper suggests, which in turn means that the genetics of longevity will be a very complex morass of a field: "The results of genome-wide association studies of complex traits, such as life span or age at onset of chronic disease, suggest that such traits are typically affected by a large number of small-effect alleles. Individually such alleles have little predictive values, therefore they were usually excluded from further analyses. The results of our study strongly suggest that the alleles with small individual effects on longevity may jointly influence life span so that the resulting influence can be both substantial and significant." Bear in mind that this may mean thousands or tens of thousands of potentially important interactions, which may differ significantly by population or individual. This is one of the many reasons that slowing down aging will likely be harder to accomplish than repairing the effects of aging: a repair strategy such as SENS doesn't depend on understanding genetic contributions to longevity. Researchers already know enough about the varied forms of biochemical damage that cause aging to make a start on repair technologies, were they so minded.

A novel way to assembled a targeted cancer therapy: "Cancer is a difficult disease to treat because it's a personal disease. Each case is unique and based on a combination of environmental and genetic factors. Conventional chemotherapy employs treatment with one or more drugs, assuming that these medicines are able to both 'diagnose' and 'treat' the affected cells. Many of the side effects experienced by chemotherapy patients are due to the fact that the drugs they are taking aren't selective enough. ... But what if we had cancer treatments that worked more like a computer program, which can perform actions based on conditional statements? Then, a treatment would kill a cell if - and only if - the cell had been diagnosed with a mutation. Only the defective cells would be destroyed, virtually eliminating unwanted side effects. ... researchers [have] created conditional small RNA molecules to perform this task. Their strategy uses characteristics that are built into our DNA and RNA to separate the diagnosis and treatment steps. ... Here's how it works: Treatment involves two different small RNAS. The first small RNA will open up if - and only if - it finds the cancer mutation. A positive 'diagnosis' exposes a signal that was previously hidden within the small RNA. Once this small RNA is open, a second small RNA binds to it, setting off a chain reaction in which these RNA molecules continue to combine to form a longer chain. The length of the chain is an important part of the 'treatment'. Longer chains trick the cell into thinking it has been invaded by a virus, tripping a self-destruct response."

The same genes in different people can produce different metabolisms, and this is largely due to epigenetics: the way in which genes express themselves to form proteins. Studies of epigenetic differences are gathering pace: "One of the most ambitious large-scale projects in Human Genetics has been launched today: Epitwin will capture the subtle epigenetic signatures that mark the differences between 5,000 twins on a scale and depth never before attempted, providing key therapeutic targets for the development of drug treatments. ... Epigenetics [explores] how the actions of genes can be temporarily modified by chemical reactions that may occur either at random or by lifestyle or diet. This effect may last several generations. The plan is to look at the methylation patterns of 20 million sites (called CpG islands) in the DNA of each twin and compare them with the patterns in the co-twin. Rather than looking at similarities as in previous studies, the team will be looking for differences that explain why many identical twins don't develop the same diseases. Initially the team will focus on obesity, diabetes, allergies, heart disease, osteoporosis and longevity, but the method can be applied to every common trait or disease. ... So far this type of study has only been attempted on a handful of twins, so we want to scale it up - one thousand fold."

You might recall that centenarian studies in the Ashkenazi population showed an association betweeen lipid metabolism and longevity. Here is another study that shows similar correlations in a different population: "Mechanisms underlying the variation in human life expectancy are largely unknown, but lipid metabolism and especially lipoprotein size was suggested to play an important role in longevity. We have performed comprehensive lipid phenotyping in the Leiden Longevity Study ... only LDL size and triglyceride levels were associated with offspring from long-lived families. Sex-specific backwards regression analysis revealed that LDL particle sizes were associated with male longevity. Triglyceride levels, but not LDL particle size, were associated with female longevity. Due to the analysis of a comprehensive lipid profile, we confirmed an important role of lipid metabolism in human longevity, with LDL size and triglyceride levels as major predicting factors." That different populations and the two genders have noticeable differences in the correlations between longevity and aspects of lipid metabolism is an indication of complexity: many factors at work under the hood.



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