"You've got to ask yourself one question: Do I feel lucky? Well, do ya, punk?" Do you feel lucky enough to carry lots of long life genetic variants?
While environment and family history are factors in healthy aging, genetic variants play a critical and complex role in conferring exceptional longevity, according to a new study by a team of researchers from the Boston University Schools of Public Health and Medicine and the Boston Medical Center.
In a study released July 1 online by the journal Science, the research team identified a group of genetic variants that can predict exceptional longevity in humans with 77 percent accuracy – a breakthrough in understanding the role of genes in determining human lifespan.
Based upon the hypothesis that exceptionally old individuals are carriers of multiple genetic variants that influence their remarkable survival, the team conducted a genome-wide association study of centenarians. Centenarians are a model of healthy aging, as the onset of disability in these individuals is generally delayed until they are well into their mid-nineties.
Unfortunately we can't pick our own genetic variants (yet). To learn today whether you have shorter or longer life genetic is more akin to learning when your death sentence will be carried out.
At least 150 genetic variants matter for your odds of living a very long time. If you could know how many of these genetic variants you carry would you want to know?
Researchers led by Paola Sebastiani, PhD, a professor of biostatistics at the BU School of Public Health and Thomas Perls, MD, MPH, associate professor of medicine at the BU School of Medicine and a geriatrician at Boston Medical Center, built a unique genetic model that includes 150 genetic variants, known as single nucleotide polymorphisms (SNPs). They found that these 150 variants could be used to predict if a person survived to very old ages (late 90s and older) with a high rate of accuracy.
In addition, the team's analysis identified 19 genetic clusters or "genetic signatures" of exceptional longevity that characterized 90 percent of the centenarians studied. The different signatures correlated with differences in the prevalence and age-of-onset of diseases such as dementia and hypertension, and may help identify key subgroups of healthy aging, the authors said.
Notably, the team found that 45 percent of the oldest centenarians – those 110 years and older – had a genetic signature with the highest proportion of longevity-associated genetic variants.
The obvious question: What could we as individuals do with this information if we could know from our genetic profile how long we had to live? My first reaction: Not much. But wait. If you knew you had decent odds of living to 100 you'd know to save more for retirement and work more years before retiring. That's a good idea anyway (what with governments unable to afford to deliver all the promises they've made for old age benefits). But accumulation of big savings is an especially good idea if your genetic profile suggests you have higher odds of living into your 90s and possibly beyond. So genetic testing as retirement planning guide. That's the ticket.
Genetic profiles that predict longevity are initially more useful for researchers. That's part of a larger pattern where the tons of DNA sequencing information hasn't turned out to be immediately useful for treating diseases but is helping researchers learn which genetic variations cause which changes in gene expression and in differences in disease risks, special abilities (e.g. ability to live at high altitudes), personality traits, intelligence, and other ways in which humans differ.
How can researchers use genetic information linked to life expectancy to help those of us not born with genes that'll make us into centenarians? I see a few ways:
I am skeptical about the drug approach mostly because, if the study above is correct, the centenarians have many genetic differences which account for their longer lives. Many differences that matter mean many drug targets which means develop many drugs to make a big difference. Each drug would cost about $1 billion to develop and each would therefore be expensive to buy month after month, year after year. Even if a few drugs could target a few of those differences the drugs still wouldn't target all the differences. Plus, drugs frequently have side effects. Plus, the drugs would have to be taken for decades to make a difference which means the tedium of taking the drugs for decades as well as dealing with side effects for decades.
Similarly, I think there's a limit to what diet can accomplish. Those old Dannon yogurt commercials aside, it doesn't look like there's a diet that will enable most people to live to 90, let alone 100.
One might expect fewer of the already known disease-associated genetic variants to be found in centenarians. But the disease-associated genetic variants did not appear to make much of an impact.
Besides looking at which genetic variants were associated with longevity, the authors looked into whether the absence of disease-associated variants also played an important role. They did this by analyzing how many disease-associated variants each centenarian had, compared to each of the controls. Their analysis found little difference between the two groups, suggesting that the presence of genetic variants associated with longevity is of more importance than the absence of disease-associated variants.
Biogerontologist Aubrey de Grey argues that we should focus our efforts on developing treatments that repair the damage caused by aging. Even if we can eventually slow down the rate of aging using drugs we'll all be older by the time those drugs hit the market and those drugs won't reverse the damage already done. At best they'll make the downhill slope from that point on not as steep as it otherwise would be. We'll still grow old just like the centenarians.
Consider the idea of gene therapy and cell therapy to alter our metabolism to slow aging. Once researchers develop workable cell therapies it seems more sensible to first apply these cell therapies to repair of damage. If we can send in replacement cells that have also been altered to last longer (by, say, first altering the cells to contain the 150 genetic variants mentioned above) then all the better. But the capability to do repairs is more important than how long the repairs will last.
In this study, the research team genotyped 40 candidate genes known to be important for synthesis and metabolism of cholesterol in people who participated in a population case-control study of colorectal cancer in northern Israel. Included were 1,780 colon cancer patients and 1,863 people who did not have colorectal cancer, and many of the participants, who were predominantly Caucasian, had used statins for a long time. In the initial study, statin use was associated with a 50 percent relative risk of developing colorectal cancer in this population.
Included in the 40 genes were six SNPs, or DNA sequences, within the HMGCR gene, which produces a critical enzyme involved in formation of cholesterol.
They found one SNP within HMGCR that was associated with statin protection against colorectal cancer. A follow-up pharmacogenetic analysis showed that the protective association was significantly stronger among individuals with what they dubbed the "A" SNP allele, or variant, compared with people who had a "T" variant. Because a person inherits two variants, one from each parent, the stronger colorectal cancer protection came from individuals with the A/A HMGCR genotype, compared with those with the T/T genotype. Individuals with an A/T genotype had intermediate protection against colorectal cancer -- levels that varied between that seen for A/A and T/T genotypes.
Since genetic variants occur in different frequencies in different populations a lot of medical research that does not control for genetic variants ends up producing conflicting results depending on the genetic endowment of experimental subjects.
“It’s the exact same mechanism for lowering cholesterol as it is for lowering colon cancer risk. This is true only for those people who are actually taking statins. The gene test by itself doesn’t predict whether you’re at an increased risk of colon cancer; it predicts only how well statins lower the risk,” Gruber says.
The researchers point out that it’s easy to know if statins are successfully lowering cholesterol, but their effect on colorectal cancer prevention is not as apparent. That’s where a gene test would come in.
Statins also cause harmful side effects in some users. If genetic testing can flag who will have bad reactions to statins and also who will have the most cancer reduction benefits then the argument for taking statins will become stronger for some while at the same time becoming much weaker for others.
This is part of a larger pattern in increased value from genetic testing. In just 5 years I expect the number of potential benefits from genetic testing to become very compelling.
Three years ago, geneticists reported the startling discovery that nearly half of all people in the U.S. with European ancestry carry a variant of the fat mass and obesity associated (FTO) gene, which causes them to gain weight — from three to seven pounds, on average — but worse, puts them at risk for obesity.
Now, UCLA researchers have found that the same gene allele, which is also carried by roughly one-quarter of U.S. Hispanics, 15 percent of African Americans and 15 percent of Asian Americans, may have another deleterious effect.
Reporting in the early online edition of the journal Proceedings of the National Academy of Sciences, senior study author Paul Thompson, a UCLA professor of neurology; lead authors April Ho and Jason Stein, graduate students in Thompson's lab; and colleagues found that the FTO variant is also associated with a loss of brain tissue. This puts more than a third of the U.S. population at risk for a variety of diseases, such as Alzheimer's.
What I wonder: If weight gain can be avoided does the brain tissue loss still happen? In other words, what's the mechanism of action for the brain loss?
If you could get yourself tested for FTO gene variants would you want to know which variant you have? It isn't clear to me what you could do with the results.
The really appealing genetic tests will be the ones that give you actionable information. For example, what's your ideal personal diet? Which foods are you at greater risk from? Knowing that you had genetic variants of enzymes for processing heterocyclic amines that put you at higher risk for cancer would let you know to not cook your meat at high temperatures. Also, not everyone gets much of a blood pressure risk from eating a lot of salt. It would be helpful to know if one should avoid salt or not. Why deprive yourself of something if deprivation isn't beneficial?
A genetic variant appears to influence the length of telomeres which are caps on chromosomes. These telomere caps shorten with age and the shortening is linked to aging.
Scientists announced today (7 Feb) they have identified for the first time definitive variants associated with biological ageing in humans. The team analyzed more than 500,000 genetic variations across the entire human genome to identify the variants which are located near a gene called TERC.
It is important to note that telomere shortening might offer a life extending benefit: shorter telomeres might stop at least some cancer cells from dividing too many times. The genetic variant that shortens telomeres therefore might have been selected for in some humans.
Shorter telomeres are linked to some diseases of old age.
"What we studied are structures called telomeres which are parts of one's chromosomes. Individuals are born with telomeres of certain length and in many cells telomeres shorten as the cells divide and age. Telomere length is therefore considered a marker of biological ageing.
"In this study what we found was that those individuals carrying a particular genetic variant had shorter telomeres i.e. looked biologically older. Given the association of shorter telomeres with age-associated diseases, the finding raises the question whether individuals carrying the variant are at greater risk of developing such diseases"
Possibly the genetic variant causes telomeres to shorten more rapidly.
Professor Tim Spector from King's College London and director of the TwinsUK study, who co-led this project, added:
"The variants identified lies near a gene called TERC which is already known to play an important role in maintaining telomere length. What our study suggests is that some people are genetically programmed to age at a faster rate. The effect was quite considerable in those with the variant, equivalent to between 3-4 years of 'biological aging" as measured by telomere length loss. Alternatively genetically susceptible people may age even faster when exposed to proven 'bad' environments for telomeres like smoking, obesity or lack of exercise – and end up several years biologically older or succumbing to more age-related diseases. "
A great way to cure cancer that has minimal side effects would open the door for a variety of rejuvenation therapies. Treatments to lengthen telomeres would carry less risk if cancer was easily curable.
Stem cell therapies hold out the hope of working around the telomere shortening problem. Old cells can accumulate dangerous genetic mutations that can lead to cancer. But in the future stem cell lines will be selected to have few harmful mutations and then stem cells with long telomeres can be inserted into the body with the ability to grow and do repairs that cells with short telomeres are unable to do.
Genetic variation in the DNA of mitochondria – the “power plants” of cells – contributes to a person’s risk of developing age-related macular degeneration (AMD), Vanderbilt investigators report May 7 in the journal PLoS ONE.
Mitochondrial genes are a logical place to expect genetic variants to influence the rate of aging. The mitochondrial DNA (mtDNA) accumulates damage and mtDNA damage is probably a major cause of aging through out the body.
The study is the first to examine the mitochondrial genome for changes associated with AMD, the leading cause of blindness in Caucasians over age 50.
“Most people don’t realize that we have two genomes,” said lead author Jeff Canter, M.D., M.P.H., an investigator in the Center for Human Genetics Research. “We have the nuclear genome – the “human genome” – that makes the cover of all the magazines, and then we also have this tiny genome in mitochondria in every cell.”
Canter teamed with Jonathan Haines, Ph.D., and Paul Sternberg, M.D., experts in AMD genetics and treatment, to examine whether a particular variation in the mitochondrial genome is associated with the disease. The genetic change occurs in about 10 percent of Caucasians, referred to as mitochondrial haplogroup T.
The tiny bit of mtDNA is much more vulnerable to damage because the mitochondria have lots of reactive chemicals in them in the process of getting converted from sugar into more useful forms of chemical energy. Some of those reactive chemicals bump into the mtDNA and cause damage that messes up energy production. But better mtDNA sequences code for mitochondrial enzymes that basically break down the sugar more cleanly with less intracellular pollution by free radicals.
Members of this team have already discovered a few other genetic variants that contribute to AMD risk.
The genetics of AMD has been a “hot” area lately, Canter said. Haines led a team that identified a variant in the Complement Factor H (CFH) gene as accounting for up to 43 percent of AMD. Variations in ApoE2 and a gene called LOC387715 on chromosome 10 have also been linked to the disease, and Haines and colleagues demonstrated an interaction between the chromosome 10 gene and smoking in raising AMD risk.
The current study also examined variation in these nuclear genes in 280 cases and 280 age-matched controls, and demonstrated that the mitochondrial genome variation was independent of the known nuclear factors.
Once cell therapy and gene therapy become practical I want to upgrade various parts of my body with stem cells that will create longer lasting tissue. We should rejuvenate our bodies. But we should also reduce the maintenance intervals. Studies such as the one above point us in the direction of how to make longer lasting components.
Genetic engineering of a mitochondrial gene in mice to generate more heat causes the mice to live longer.
By making the skeletal muscles of mice use energy less efficiently, researchers report in the December issue of Cell Metabolism, a publication of Cell Press, that they have delayed the animals’ deaths and their development of age-related diseases, including vascular disease, obesity, and one form of cancer. Those health benefits, driven by an increased metabolic rate, appear to come without any direct influence on the aging process itself, according to the researchers.
The mitochondria powering the mouse muscles were made inefficient by increasing the activity of so-called uncoupling protein 1 (UCP1). UCP1 disrupts the transfer of electrons from food to oxygen, a process known as mitochondrial respiration, which normally yields the energy transport molecule ATP. Instead, the energy is lost as heat.
“When you make the mitochondria inefficient, the muscles burn more calories,” a metabolic increase that could be at least a partial substitute for exercise, said Clay Semenkovich of Washington University School of Medicine in St. Louis. “There are a couple of ways to treat obesity and related diseases,” he continued. “You can eat less, but that’s unpopular, or you could eat what you want as these animals did and introduce an altered physiology. It’s a fundamentally different way of addressing the problem.”
This result suggests that the development of drugs to cause the same effect in humans might increase human longevity.
This genetic alteration produced many beneficial effects.
In the new study, Semenkovich’s group used these mice to determine whether respiratory uncoupling in skeletal muscle—a tissue that adapts to altered heat production and oxygen consumption during exercise—can affect age-related disease. They found that animals with increased UCP1 only in skeletal muscle lived longer. Altered female animals also developed lymphoma, a type of cancer that originates in white blood cells called lymphocytes, less frequently. In mice genetically predisposed to vascular disease, the increase in UCP1 led to a decline in atherosclerosis in animals fed a “western-type” high-fat diet. Likewise, mice predisposed to developing diabetes and hypertension were relieved of those ailments by increased UCP1 in skeletal muscle. The “uncoupled mice” also had less body fat (or adiposity) and higher body temperatures and metabolic rates, among other biochemical changes.
I would rather have a version of UCP1 that I could switch between different levels of efficiency. Before going on a hike or after an accident or natural disaster it might make sense to shift UCP1 into a more efficient form. Basically, burn off excess energy when you can afford to do so but put your body into a high efficiency mode of operation when the need arises.
The development of drugs that reduce appetite should eventually reduce the benefit of turning UCP1 into a less efficient form. No need to burn off excess sugars and fats if you can make your brain not crave calories in the first place.
Your genes seem like they are at war with each other. Very old ld people have genetic variations that protect them against other genetic variations they have.
August 24, 2007 – (BRONX, NY) – People who live to 100 or more are known to have just as many—and sometimes even more—harmful gene variants compared with younger people. Now, scientists at the Albert Einstein College of Medicine of Yeshiva University have discovered the secret behind this paradox: favorable “longevity” genes that protect very old people from the bad genes’ harmful effects. The novel method used by the researchers could lead to new drugs to protect against age-related diseases.
Next time someone marvels to you about the design of the human eye (which is really dumb if you look at the way nerves are routed to the light sensors called rods and cones) or other aspects of human anatomy keep in mind that you contain genetic variations that are bad for your health.
“We hypothesized that people living to 100 and beyond must be buffered by genes that interact with disease-causing genes to negate their effects,” says Dr. Aviv Bergman, a professor in the departments of pathology and neuroscience at Einstein and senior author of the study, which appears in the August 31 issue of PLoS Computational Biology.
A group of researchers are studying the genetics of some long-lived Ashkenazi Jews.
To test this hypothesis, Dr. Bergman and his colleagues examined individuals enrolled in Einstein’s Longevity Genes Project, initiated in 1998 to investigate longevity genes in a selected population: Ashkenazi (Eastern European) Jews. They are descended from a founder group of just 30,000 or so people. So they are relatively genetically homogenous, which simplifies the challenge of associating traits (in this case, age-related diseases and longevity) with the genes that determine them.
Participating in the study were 305 Ashkenazi Jews more than 95 years old and a control group of 408 unrelated Ashkenazi Jews. (Centenarians are so rare in human populations—only one in 10,000 people live to be 100—that “longevity” genes probably wouldn’t turn up in a typical control group. Longevity runs in families, so 430 children of centenarians were added to the control group to increase the number of favorable genes.)
The scale of their study was pretty limited. First, they only had 305 very old Ashkenazi Jews. Plus, they only looked at 66 genetic markers.
All participants were grouped into cohorts representing each decade of lifespan from the 50’s on up. Using DNA samples, the researchers determined the prevalence in each cohort of 66 genetic markers present in 36 genes associated with aging.
A far larger study with more centenarians and thousands of genetic markers tested would likely turn up many more genetic variations of interest. I repeat: We need a massive study of centenarian genetics that compares the entire genome of long lived and less long lived to find out which genetic variations boost life expectancy.
The researchers think they found a genetic variant of one gene, cholesteryl ester transfer protein (CETP), that protects against the genetic variant of another gene which codes for a lipoprotein, lipoprotein a (aka Lp(a)).
As expected, some disease-related gene variants were as prevalent or even more prevalent in the oldest cohorts of Ashkenazi Jews than in the younger ones. And as Dr. Bergman had predicted, genes associated with longevity also became more common in each succeeding cohort. “These results indicate that the frequency of deleterious genotypes may increase among people who live to extremely old ages because their protective genes allow these disease-related genes to accumulate,” says Dr. Bergman. The Einstein researchers were able to construct a network of gene interactions that contributes to the understanding of longevity. In particular, they found that the favorable variant of the gene CETP acts to buffer the harmful effects of the disease-causing gene Lp(a).
Elevated blood plasma Lp(a) is associated with increased risk of stroke and heart disease. That a CETP variant could reduce the risk posed by Lp(a) is not surprising. CETP variants appear to affect the size of LDL cholesterol particles and other research shows other influences that CETP has on apolipoprotein A1 concentrations.
We need much larger scale studies of centenarian gene expression and gene sequences to find genetic reasons why they live longer. We can use that knowledge to target genes for drug development. If genetic variations cause higher levels of expression of genes that turn out to allow us to live longer then we need to find out which genes those are and try to develop drugs that will turn up those genes. We also need drugs that will turn down the activity of genes that appear to accelerate aging.
The knowledge about which genes enable us to live longer only will allow us to slow the rate of aging. What we need even more are biotechnologies that let us reverse aging and rejuvenate the body. In particular, what I most want are stem cell therapies and tissue engineering technologies. Also, we need gene therapies and nanobots to use to repair the brain.
Whether it is safe or harmful to pig out on large amounts of french fries cooked in corn oil may depend on which genetic variation of apolipoprotein A5 (APOA5) that you carry. People who carry the wrong APOA5 version and eat more than 6% of their calories from omega 6 fatty acids get high triglycerides and other bad blood lipid components.
Boston -- Researchers from the Jean Mayer USDA Human Nutrition Research Center (USDA HNRCA) at Tufts University and colleagues have found another link among genes, heart disease and diet. The study, published in Circulation, examined apolipoprotein A5 (APOA5), a gene that codes for a protein, which in turn plays a role in the metabolism of fats in the blood. The results show that people who carry a particular variant of APOA5 may have elevated risk factors that are associated with heart disease, but only if they also consumed high amounts of omega-6 fatty acids in their diets.
Corresponding author Chao-Qiang Lai, PhD, a USDA-Agricultural Research Service (ARS) scientist at the USDA HNRCA, and colleagues analyzed lipid levels and dietary assessment questionnaires of more than 2,000 participants in the Framingham Heart Study and quantified their intake of different types of fats.
Omega-6 fatty acids, as well as omega-3 fatty acids, are polyunsaturated fatty acids (PUFAs) and, according to a report from the National Institutes of Health Office of Dietary Supplements, most Americans consume about 10 times more omega-6s than omega-3s. Omega-3s are found in nuts, leafy green vegetables, fatty fish, and vegetable oils like canola and flaxseed, while omega-6s are found in grains, meats, vegetable oils like corn and soy, and also processed foods made with these oils. Both omega-3s and omega-6s, known as essential fatty acids, must be consumed in the diet because they are not made by the body.
"We know that some people are genetically predisposed to risk factors for heart disease, such as elevated low-density lipoprotein levels in the blood," says Lai, "and that APOA5 has an important role in lipoprotein metabolism. We wanted to determine if certain dietary factors change the role of APOA5 in metabolizing these lipoproteins and their components, such as triglycerides."
Lai and colleagues found that approximately 13 percent of both men and women in the study were carriers of the gene variant. Those individuals that consumed more than six percent of daily calories from omega-6 fatty acids displayed a blood lipid profile more prone to atherosclerosis (hardening of the arteries) and heart disease, including higher triglyceride levels.
The ability to get the DNA sequence of all your genome is starting to become useful. The information is starting to become practically useful for individuals and not just useful for scientists. DNA sequencing still costs orders of magnitude too much money. But the cost of getting a small subset of genes checked for problematic genetic sequences is much more affordable.
(Philadelphia, PA) - Building on previous work, researchers at the University of Pennsylvania School of Medicine have found that deleting an inflammation enzyme in a mouse model of heart disease slowed the development of atherosclerosis. What's more, the composition of the animals' blood vessels showed that the disease process had not only slowed, but also stabilized. This study points to the possibility of a new class of nonsteroidal anti-inflammatory drugs (NSAIDs) that steer clear of heart-disease risk and work to reduce it.
Drugs that block the same gene (or its protein product) that was knocked out in these mice might also stop the development of arterial plaque that clogs up our circulatory systems. Mouse knock-out experiments once again deliver the goods.
Senior author Garret FitzGerald, MD, Director of the Institute for Translational Medicine and Therapeutics at Penn, and colleagues report their findings this week in the online edition of the Proceedings of the National Academy of Sciences.
NSAIDs like ibuprofen (Advil) and naproxen (Naprosyn) relieve pain and inflammation by blocking the cyclooxygenases, or COX enzymes (COX-1 and COX-2). These enzymes help make fats called prostaglandins. COX-2 is the most important source of the two prostaglandins - PGE2 and prostacyclin - that mediate pain and inflammation. However, COX-2-derived PGE2 and prostacyclin may also protect the heart, and loss of this function - particularly suppression of prostacyclin - explains the risk of heart attacks from NSAIDs that inhibit COX-2, such as rofecoxib (Vioxx), valdecoxib (Bextra), and celecoxib (Celebrex).
The problems with COX-2 inhibitors have prompted the search for alternative drug targets that suppress pain and inflammation yet are safe for the cardiovascular system. One possibility is an enzyme called mPGES-1, which converts PGH2 (a chemical product of COX-2) into PGE2. Previous studies at other institutions in mice lacking mPGES-1 suggest that inhibitors of this enzyme might retain much of the effectiveness of NSAIDs in combating pain and inflammation. However, unlike COX-2 inhibition or deletion, the Penn researchers had found that mPGES-1 deletion did not elevate blood pressure or predispose the mice to thrombosis. This work began to raise the possibility that mPGES-1 inhibitors might even benefit the heart.
In the PNAS study, the researchers studied the impact of deleting the mPGES-1 gene in mice predisposed to hardening of the arteries. Removing the enzyme had a dramatic effect on the development of the disease. "Both male and female mice slowed their development of atherosclerosis," explains first author Miao Wang, PhD, a postdoctoral fellow in the Penn Institute.
The composition of the blood vessels of the transgenic mice suggested that the disease process had not only slowed, but also stabilized. Collaborators Ellen Pure and Alicia Zukas at the Wistar Institute examined the detailed structure of the diseased arteries. Deleting mPGES-1 resulted in a dramatic change in the cellular constituents of the atherosclerotic plaques seen in the transgenic mice. In the absence of the enzyme, the diseased vessels were depleted of immune cells called macrophages, which led to the predominance of vascular smooth muscle cells in blood vessel walls. In turn, this led to a switch in the form of collagen - a fibrous structure that contributes to the fabric of plaques - to a more stable and benign form.
"It seems that it is the complete reverse of the mechanism that creates problems for COX-2 inhibitors," says FitzGerald. Mice lacking mPGES-1 boost their production of prostacyclin, the major heart-protecting fat produced by COX-2. They do this by redirecting prostacylcin to vascular smooth muscle cells. The same mechanism explains the group's earlier findings on blood pressure and thrombosis.
"It remains to be determined whether specific inhibitors of mPGES-1 can replicate the consequences of removing the gene" explains FitzGerald, "And if so, whether these results will translate from mice to humans."
In the meantime, these results, say the investigators, will fuel interest in the possibility of a new class of "super NSAIDs," which may not just avoid the risk of heart disease, but also actually work to diminish it.
The build-up of artery plaque is going to become totally preventable and in short order. Diet alone already can reduce the risk enormously. Eat the ape diet if you want to lower your risk of heart disease, stroke and other diseases..
University of California, Davis researchers have shown that statins not only improve cholesterol levels, but also dramatically reduce disease-causing inflammation in patients with metabolic syndrome -- a condition defined by symptoms that include abdominal obesity and high blood pressure.
The UC Davis team conducted a double-blind, randomized, placebo-controlled study in which they gave a standard daily dose of a statin (Simvastatin or placebo) to 50 patients with metabolic syndrome. After eight weeks, they measured cholesterol levels, as well as biomarkers of inflammation in the circulation, but more importantly, in cells pivotal in all stages of plaque formation, the monocytes. They found, as expected, that statin lowered low-density-lipoprotein- cholesterol and non-high-density-lipoprotein-cholesterol levels, both of which the American Heart Association guidelines target for treatment of metabolic syndrome.
Jialal and his colleagues also found marked reductions in two pivotal biomarkers of inflammation: C-reactive protein (CRP) and interleukin-6. While these markers are typically elevated in insulin resistance, a condition that precedes the development of diabetes, statin therapy reduced these levels by 36 percent and 44 percent, respectively.
Chronic inflammation is harmful and widespread.
As for people who have a need to take one of the existing NSAIDs, a recent pair of papers in the Journal of the American Medical Association found that Celebrex does not pose as large of a heart risk as Vioxx.
In one paper, three researchers at Harvard examined 114 clinical trials of Vioxx and other drugs and found that Vioxx was linked to substantially higher rates of increased blood pressure than was Celebrex, a similar painkiller, which is still sold.
In the other paper, two Australian researchers found that Vioxx appeared more dangerous than Celebrex or several older painkillers in observational studies, which examine the safety and effectiveness of drugs in real-world settings after they are approved.
David Graham of the FDA, writing as a private citizen, argues in JAMA that naproxen appears safest out of all the NSAIDs and probably is neutral in terms of risk of heart attack (MI or myocardial infarction).
The New York Times has an excellent article surveying what is known about the role genetic inheritence in determining life expectancy and mortality. Recent studies on twins point toward a much smaller than expected role for genetics in determing life expectancy.
His solution, a classic one in science, was to study twins. The idea was to compare identical twins, who share all their genes, with fraternal twins, who share some of them. To do this, Dr. Christensen and his colleagues took advantage of detailed registries that included all the twins in Denmark, Finland and Switzerland born from 1870 to 1910. That study followed the twins until 2004 to 2005, when nearly all had died.
Now, Dr. Christensen and his colleagues have analyzed the data. They restricted themselves to twins of the same sex, which obviated the problem that women tend to live longer than men. That left them with 10,251 pairs of same-sex twins, identical or fraternal. And that was enough for meaningful analyses even at the highest ages. “We were able to disentangle the genetic component,” Dr. Christensen said.
But the genetic influence was much smaller than most people, even most scientists, had assumed. The researchers reported their findings in a recent paper published in Human Genetics. Identical twins were slightly closer in age when they died than were fraternal twins.
But, Dr. Christensen said, even with identical twins, “the vast majority die years apart.”
On average identical twins die over 10 years apart. I would not have expected that result.
Even the role for genetic inheritance for cancer risk differences is seen as fairly small.
In a paper in The New England Journal of Medicine in 2000, Dr. Paul Lichtenstein of the Karolinska Institute in Stockholm and his colleagues analyzed cancer rates in 44,788 pairs of Nordic twins. They found that only a few cancers — breast, prostate and colorectal — had a noticeable genetic component. And it was not much. If one identical twin got one of those cancers, the chance that the other twin would get it was generally less than 15 percent, about five times the risk for the average person but not a very big risk over all.
Of course there are people who have genetic variations which put them at very high risk of cancer.
Alzheimer's risk has a larger genetic component.
Dr. Gatz and Dr. Pedersen analyzed data from a study of identical and fraternal Swedish twins 65 and older. If one of a pair of identical twins developed Alzheimer’s disease, the other had a 60 percent chance of getting it. If one of a pair of fraternal twins, who are related like other brothers and sisters, got Alzheimer’s, the other had a 30 percent chance of getting it.
But, Dr. Pedersen noted, Alzheimer’s is so common in the elderly that it occurs in 35 percent of people age 80 and older.
Note there are some complicating factors here. Most notably, some genetic variations put you at risk for some disease only if you do or do not do some certain thing. For example, a genetic variation for apolipoprotein E increases risk of Alzheimer's but if you have that apoliprotein E allele then diet can greatly reduce the risk. So if you live in a culture where the customary foods cancel out the genetic risk you aren't going to be at much greater risk from that genetic allele. But if you live in a culture where you eat customary foods which do not provide compensating protections then carrying that genetic allele will put you at much greater risk of Alzheimer's.
One theory of aging and longevity is that we randomly collect defects and damage during development and also during aging. Given that the process of collecting those defects is random their distribution is random. If you are lucky your defects will accumulate with a fairly even distribution throughout the body. That way it will take longer for one organ to collect enough defects to fail entirely. But if you are unlucky then by chance many of your defects will accumulate in one organ or one part of an organ (e.g. in a heart valve) or in one cell (e.g. a set of mutations that make the cell become cancerous) to the point of failure and then you'll die sooner. Twins won't live the same amount of time because they each will accumulate defects in a different random distribution.
So what's the take-away lesson from this article? There's no reason for complacency about your life expectancy. Say your parents or grandparents lived a long time. So what. That's no guarantee you won't get cancer tomorrow or have a heart attack next week. Your defects are accumulating randomly. You might be accumulating a cluster somewhere that is going to kill you years before other family members die. If you want to live a very long time then support SENS research. Anything short of SENS technologies can't save you from the damage building up within.
The whole article is worth reading.
STANFORD — We can dye gray hair, lift sagging skin or boost lost hearing, but no visit to the day spa would be able to hide a newly discovered genetic marker for the toll that time takes on our cells. “We’ve found something that is at the core of aging,” said Stuart Kim, PhD, professor of developmental biology and of genetics at the Stanford University School of Medicine.
In a study published in the July 21 issue of Public Library of Science-Genetics, Kim and colleagues report finding a group of genes that are consistently less active in older animals across a variety of species. The activity of these genes proved to be a consistent indicator of how far a cell had progressed toward its eventual demise.
Until now, researchers have studied genes that underlie aging in a single animal, such as flies or mice, or in different human tissues. However, a protein associated with aging in one species may not be relevant to the aging function in a different animal. This limitation had made it difficult to study the universal processes involved in aging.
Kim’s work overturns a commonly held view that all animals, including humans, age like an abandoned home. Slowly but surely the windows break, the shingles fall off and floorboards rot, but there’s no master plan for the decay.
What we need to know: Which genes first start changing? Or which key regulatory switches start telling genes to start expressing differently? To put it more generally: What is the sequence of events that causes the genes to start behaving differently with age?
One possibility: The genes in the mitochondria (the sub-cellular organelles that generate energy molecules for the rest of the cell) could get mutated and damaged and then the genes in the nucleus start expressing differently due to signals coming out of the mitochondria.
Energy metablolism takes a big hit with age.
In the study, Kim and his colleagues looked at which genes were actively producing protein and at what level in flies and mice in a range of ages and in tissue taken from the muscle, brain and kidney of 81 people ranging in age from 20 to 80. The group used a microarray, which can detect the activity level of all genes in a cell or tissue. Genes that are more active are thought to be making more proteins.
One group of genes consistently made less protein as cells aged in all of the animals and tissues the group examined. These genes make up the cellular machinery called the electron transport chain, which generates energy in the cell’s mitochondria.
Kim said the gene activity is a better indicator of a cell’s relative maturity than a person’s birthday. One 41-year-old participant had gene activity similar to that of people 10 to 20 years older; muscle tissue from the participant also appeared similar to that of older people. Likewise, the sample from a 64-year-old participant, whose muscles looked like those of a person 30 years younger, also showed gene activity patterns similar to a younger person.
Biopsies of many organs in your body might tell you which organs are going to wear out first and which need replacements. With the sort of biotechnology we'll have 10 or 20 years from now we'll be able to start growing replacements for the worn out parts. Ideally, the replacements could be grown inside your own body and then connected up with surgery.
You can read the full article online: Transcriptional Profiling of Aging in Human Muscle Reveals a Common Aging Signature
We analyzed expression of 81 normal muscle samples from humans of varying ages, and have identified a molecular profile for aging consisting of 250 age-regulated genes. This molecular profile correlates not only with chronological age but also with a measure of physiological age. We compared the transcriptional profile of muscle aging to previous transcriptional profiles of aging in the kidney and the brain, and found a common signature for aging in these diverse human tissues. The common aging signature consists of six genetic pathways; four pathways increase expression with age (genes in the extracellular matrix, genes involved in cell growth, genes encoding factors involved in complement activation, and genes encoding components of the cytosolic ribosome), while two pathways decrease expression with age (genes involved in chloride transport and genes encoding subunits of the mitochondrial electron transport chain). We also compared transcriptional profiles of aging in humans to those of the mouse and fly, and found that the electron transport chain pathway decreases expression with age in all three organisms, suggesting that this may be a public marker for aging across species.
People who had worse muscle function also had gene expression patterns characteristic of more aged muscles.
The authors profiled gene expression changes in the muscles of 81 individuals with ages spanning eight decades. They found 250 genes and 3 genetic pathways that displayed altered levels of expression in the elderly. The transcriptional profile of age-regulated genes was able to discern elderly patients with severe muscle aging from those that retained high levels of muscle function; that is, the gene expression profiles reflected physiological as well as chronological age.
Another use for this information: Study people on different diets and lifestyles and see if particular diets or patterns of living cause particular organs to age more rapidly.
Some day I expect spouses to include DNA tests on body aging to argue that their spouses are aging them too rapidly.