2010 April 21 Wednesday
COMT Gene Influences Brain Aging

A gene that breaks down degrade catecholamines such as dopamine, epinephrine, and norepinephrine (all neurotransmitters) has variants that influence brain aging and brain performance. The variants come with trade-offs.

For the study, researchers followed 2,858 African-American and Caucasian people between the ages of 70 and 79 for eight years. Participants’ DNA was analyzed for the catechol-O-methyltransferase (COMT) gene, a gene shown in studies to affect thinking skills. The allelic variants associated with this gene are the Val and Met variants.

The group was also given two types of thinking tests. One test measured skills such as language, concentration and memory. The other test measured response time, attention and judging sights and objects.

The study found that the Met variant of the COMT gene was linked to a greater decline in thinking skills over the years, while the Val variant had a protective effect on thinking skills, with lower declines over the years. In Caucasians, those with the Val variant scored 33 percent better over time than those without the variant. Among African-Americans, people with the Val allele gene variant scored 45 percent better over time than those who did not have the variant.

Slower aging makes the Val variant sound appealing, right? But the Met variant seems better at younger ages. So then is the Val variant keeping the brain younger longer by lowering brain performance at earlier stages in life?

“This finding is interesting because in younger people, the Val genotype has been shown to have a detrimental effect,” Fiocco said. “But in our study of older people, the reverse was true. Finding connections between this gene, its variants and cognitive function may help scientists find new treatments for the prevention of cognitive decline.” Fiocco added, however, that the results need to be replicated by others before the field can be confident that the Met variant of the COMT gene plays a role in late life cognitive decline.

These results underscore the trade-offs in genetic variants. Beneficial mutations often don't just boost functions. They provide benefits at a cost. Whether the benefits outweighed the costs in the past does not determine whether the benefits outweigh the costs today. Many humans have mutations (e.g. sickle cell anemia and beta thalassemia against malaria) that beneficial in the past but only harmful in their present circumstances. Still other genetic variants of other genes still provide both benefits and costs today.

By Randall Parker    2010 April 21 11:21 PM   Entry Permalink | Comments (1)
2009 July 18 Saturday
Alzheimer's Genetic Variant Acclerates Brain Aging

A genetic variant that boosts Alzheimer's Disease risk also accelerates aging of the brain. A new study led by Mayo Clinic researchers and published in the New England Journal of Medicine APOE e4 gene carriers showed a faster cognitive decline starting in their mid-50s.

The study, which followed participants for up to 14 years, used sensitive memory and thinking tests to detect, track and compare cognitive performance in 815 healthy people, 21 to 97 years of age, with two copies, one copy and no copies of the APOE e4 gene, the major genetic risk factor for developing Alzheimer's disease at older ages. Each additional copy of this gene is associated with a higher risk of Alzheimer's disease and a slightly younger age at the onset of clinically significant memory and thinking problems.

Approximately one out of four people have one copy of the APOE e4 gene, which was inherited from one parent, and about 2 percent have two copies, which were inherited from both parents.

"We found that memory declines begin to differentiate groups of people at these three levels of genetic risk starting between ages 55 and 60, years earlier than previously suspected, and well before the anticipated onset of clinically significant symptoms," said Richard J. Caselli, M.D., Chair of Mayo Clinic's Neurology Department in Arizona and lead author of the research study. "While other age-sensitive cognitive skills also change, memory, specifically, appears to decline more quickly in APOE e4 gene carriers, and it is this pattern of cognitive aging that is similar to (but much milder than) what we expect to see in patients with Alzheimer's disease. This suggests that seemingly normal age-related memory loss may actually represent very early, preclinical-stage Alzheimer's disease."

Regardless of whether you have this genetic variant all the dietary advice for reducing Alzheimer's risk still applies.

What's the big picture here? Brain aging is the worst part of aging because it slowly takes your own mind away while you still live. We need repair and rejuvenation therapies for the brain. Some of us are going to live to see the development of these therapies. Support their development. What's at stake with rejuvenation therapy development is far greater than with the vast bulk of what we see reported on the news. We need much better therapies far more than we need more delivery of existing therapies because existing therapies can not fix most of what goes wrong with us. Keep that in mind as you listen to health care debates.

By Randall Parker    2009 July 18 07:33 PM   Entry Permalink | Comments (2)
2008 November 14 Friday
Alzheimers Risk Gene Hobbles Ability Of Cells To Expel Junk

A genetic variation that boosts Alzheimer's also reduces the ability of cells to expel toxic compounds.

The only known genetic risk factor for Alzheimer's disease slows down the brain's ability to export a toxic protein known as amyloid-beta that is central to the damage the disease causes, scientists have found.

The research, published Nov. 13 by the Journal of Clinical Investigation, provides new clues into the workings of a protein known as apolipoprotein E4, or ApoE4. People who carry two copies of the gene have roughly eight to 10 times the risk of getting Alzheimer's disease than people who do not.

The new results mark a step toward resolving a longstanding question that scientists have had about exactly how ApoE4 increases a person's risk for the disease. The findings point to differences in the way that amyloid-beta is removed from the brain depending on which ApoE protein is involved.

Scientists found that when ApoE4 is present, the brain is less efficient at ridding itself of the toxic material, because a molecule that is much slower at removing the substance becomes much more involved.

Biogerontologist Aubrey de Grey argues that one of the major causes of cellular aging is the accumulation of toxic junk inside of aging cells. The body lacks enzymes to break down some kinds of intracellular junk. Therefore Aubrey argues for development of therapies to transplant into aging human cells the genes for enzymes that break down intracellular junk in other species. This report that Alzheimer's risk is boosted by a gene involved in intracellular trash removal underscores the importance of intracellular trash accumulation in brain aging. If we could remove more of the trash that accumulates in cells as we age then we wouldn't age as rapidly.

By Randall Parker    2008 November 14 12:58 AM   Entry Permalink | Comments (1)
2007 January 14 Sunday
SORL1 Genetic Risks For Alzheimer's Disease

Want to know if you'll slowly lose all your memory and control of your body in your 70s and 80s? Probably not. Hopefully a cure for Alzheimer's won't take more than 10 or 15 years and any genetic risk you have for Alzheimer's will never get a chance to slowly destroy your mind. . But if you want to know if you are at risk a research team has identified yet another genetic variation that increases the risk of late-onset Alzheimer's Disease.

Researchers led by Howard Hughes Medical Institute (HHMI) international research scholar Peter St George-Hyslop have identified a new genetic risk factor associated with the most common form of Alzheimer's disease. The research implicates a gene called SORL1 in late-onset Alzheimer's, which usually strikes after age 65.

In an advance online publication in Nature Genetics on January 14, 2007, St George-Hyslop and colleagues connected the gene to the disease in six different groups of people, although they did not pinpoint the exact genetic mutations in SORL1 responsible for Alzheimer's. In their studies, the researchers used databases that include genetic information about people with and without Alzheimer’s disease. More than 6,800 individuals—45.8 percent of them affected with the disease—were included in the analysis, which is considered a large data set in the field, said St George-Hyslop..

These SORL1 variations join apolipoprotein E variation ApoE4 as known genetic risks for late onset Alzheimer's.

“We looked for variations of SORL1 in nine different groups of people and found those variations to be associated with an increased risk of Alzheimer's in six of them,” St George-Hyslop said. “That implies that SORL1 is not the only cause of Alzheimer's, but it's one of several. Some people with the disease will have a SORL1-related cause, and some won't.” St George-Hyslop is a professor in the department of medicine and director of the Center for Research in Neurodegenerative Disease at the University of Toronto and an HHMI international research scholar. Through its international research scholars program, HHMI supports leading scientists in 28 countries outside the United States.

The researchers studied several groups of Caucasians, one group of African Americans, one group of Hispanics from the Dominican Republic, and a group of Israeli Arabs. They tracked the SORL1 genes via single nucleotide polymorphisms, or SNPs, which are single-letter changes in a gene's sequence. They found that the Caucasians with Alzheimer's displayed a certain SNP signature at one end of the gene, while the African Americans, Hispanics, and Israeli Arabs with the disease displayed another SNP signature. “This implies that there are at least two, and possibly more, gene variants at work here,” said St George-Hyslop. “That's not unusual—in many diseases you see multiple variations that all impact a specific gene.”

So how can the scientists know that a gene has a genetic variation that contributes to a disease without knowing which particular genetic variation is responsible? See the mention of SNPs (single nucleotide polymorphisms) above. Those are locations in the genome where groups of people have single letter differences in their DNA as compared to all other groups of people. SNPs tend to occur in groups. Suppose at a particular location you have a letter A in your genome. Suppose other people have a G in that location and those who have a G have greater risk of Alzheimer's. That G usually will occur along with a group of other SNPs in nearby locations. The A at the same location will occur with letters at the same nearby SNP locations. The puzzle is to figure out which of other other nearby SNPs is the one that contributes to a disease risk.

The cost of testing for SNPs in genes is declining because chips are coming to market that can test for the presence of hundreds of thousands of SNPs at a time. The decline in SNP testing costs is enabling a growing flood of successful searches for genetic variations that contribute to disease risks. Within 5 years time I expect the number of discovered and easily testable genetic risk factors will become large enough to make personal DNA testing worthwhile.

But which risks will be worth testing for? Those you'll be able to do something about. Suppose a genetic variation makes Alzheimer's inevitable at middle age and that diet has little influence on when you'll get it. Well, I guess you could decide to avoid taking on family responsibilities that you won't be around to fulfill. But initially the biggest potential for doing something about a risk will involve risks that can be influenced by diet or exercise. What we need: genetic sample collection on big population studies of diets and lifestyles. Existing on-going longitudinal studies of diet and lifestyle risks could have their diet and lifestyle information compared against disease outcomes for those with high genetic disease risk to see if any dietary factors delayed or reduced the risk of major diseases.

What you should do when you discover 5 or 10 years hence that you have high genetic risk of a disease: Write your elected officials and argue for more research on the disease you are on course to get. Lobby for cures for diseases that will otherwise kill you and your loved ones.

Update: If the result with SORL1 is replicated it will join 14 other genes which have variations which are known risk factors for Alzheimer's.

Two geneticists at Massachusetts General Hospital, Lars Bertram and Rudolph Tanzi, have tried to bring order to this confused field by combining the data from many different studies. In an article in Nature Genetics earlier this month, they presented a group of 13 genes besides apolipoprotein E that have a statistically significant association with Alzheimer’s.

Dr. Tanzi said that he had run the numbers on SORL1 and that it would qualify at present for a place in his canon. “This is another gene worth paying attention to,” he added, “but we really have to wait for more replications.”

Over on the Gene Expression blog Amnestic points to evidence that APOE4 boosts episodic memory when young at the expense of greater Alzheimer's risk when you get old. APOE4 might be a variation worth having for someone being born now. The short term advantage might not cost you anything in the long run becaus 50 years from now Alzheimer's will be easily preventable.

We are going to find that many genetic variations which increase disease risks also provide benefits. The task of choosing ideal genetic variations for offspring will not be straightforward with a simple list of good genes and another list of bad genes. The best trade-offs will depend on guesses about the future availability of technologies, guesses about the shape of future societies, and one's values.

By Randall Parker    2007 January 14 03:26 PM   Entry Permalink | Comments (0)
2007 January 03 Wednesday
Herpes Virus And ApoE Gene Cause Alzheimer's RIsk

The ApoE-4 version of the ApoE gene which is associated with a higher Alzheimer's Disease risk probably increase the risk of Alzheimer's by doing a poorer job of suppressing the Herpes virus that causes cold sores.

A gene known to be a major risk factor for Alzheimer's disease puts out the welcome mat for the virus that causes cold sores, allowing the virus to be more active in the brain compared to other forms of the gene. The new findings, published online in the journal Neurobiology of Aging, add some scientific heft to the idea, long suspected by some scientists, that herpes somehow plays a role in bringing about Alzheimer's disease.

The work links a form of the ApoE gene known as ApoE-4, which after advanced age is the leading known risk factor for getting Alzheimer's disease, with the form of herpes – herpes simplex 1 or HSV – that infects more than 80 percent of Americans and causes cold sores around the mouth. The findings from a group at the University of Rochester Medical Center show that the particular form of the gene that puts people at risk also creates a fertile environment for herpes in the brain, allowing the virus to be more active than other forms of the ApoE gene permit.

We need vaccines that will prevent Herpes virus infections. We also need drugs or perhaps gene therapies that'll suppress or kill Herpes in the brain and peripheral nerves.

Scientists have known for more than 15 years that the ApoE-4 gene is a player in Alzheimer's disease, but the idea that it works in concert with the herpes virus is new.

Note how we've known about the ApoE-4 link to Alzheimer's for 15 years without being able to do anything about it. That's true with many other genetic variations which have known roles in causing diseases. We lack the gene therapy technologies to intervene. Though the knowledge that specific genes play roles in development of diseases does allow many scientists to focus their attention on how those those operate and how their role may help cause diseases.

Different lines of evidence point toward an Apo-E4 plus Herpes connection with Alzheimer's.

Ruth Itzhaki of the University of Manchester has led the way with several studies showing a correlation between herpes and Alzheimer's. She has shown that Alzheimer's patients who have the ApoE-4 form of the gene have more herpes DNA in the brain regions that are affected by Alzheimer's, compared to Alzheimer's patients who also have herpes but who have a different form of the ApoE gene. And she has shown that people with the ApoE-4 version of the gene who are infected with herpes are more likely to get Alzheimer's disease than people infected with herpes who have a different form of the ApoE gene, or than people who have the ApoE-4 gene but who don't have herpes.

Other scientists have found that a herpes infection is active more often – causing the tell-tale cold sores around the mouth – in the 25 percent of people who have a copy of the ApoE-4 gene. In other words, people who are frequently troubled by cold sores are more likely to have the gene that makes them more vulnerable to Alzheimer's disease.

Every time you get a cold sore do you suffer mild brain damage? Seems plausible at least.

ApoE-4 does not increase the odds of infection but it does increase the amount of time time the virus is active.

The team found that the virus infiltrates brain cells about the same no matter which gene is involved. But they found that the subsequent activity level of the virus generally mirrored the disease-causing potential of the gene. They found that in animals with the ApoE-4 gene, the virus is less likely to be in the quiet, latent stage of its life cycle, suggesting it has more of an opportunity to replicate. In animals with the ApoE-2 gene, the virus was less active.

Brain aging is the form of aging I most want to slow down and delay. How to rejuvenate the 100 billion neurons in the brain is the hardest task facing rejuvenation medicine. We'll be able to reverse the aging of the rest of the body before we develop the ability to make the brain youthful once again. Therefore any treatments we can come up with to slow brain aging will provide great benefits and give us more time to develop brain rejuvenation therapies.

By Randall Parker    2007 January 03 09:59 PM   Entry Permalink | Comments (1)
2006 December 29 Friday
CETP Gene Variant Slows Brain Aging

A variation in the enzyme cholesterol ester transfer protein (CETP) slows general aging and brain aging.

ST. PAUL, Minn -- A gene variation that helps people live into their 90s and beyond also protects their memories and ability to think and learn new information, according to a study published in the December 26, 2006, issue of Neurology, the scientific journal of the American Academy of Neurology.

The gene variant alters the cholesterol particles in the blood, making them bigger than normal. Researchers believe that smaller particles can more easily lodge themselves in blood vessel linings, leading to the fatty buildup that can cause heart attacks and strokes.

The study examined 158 people of Ashkenazi, or Eastern European, Jewish descent, who were 95 years old or older. Those who had the gene variant were twice as likely to have good brain function compared to those who did not have the gene variant. The researchers also validated these findings in a group of 124 Ashkenazi Jews who were between age 75 and 85 and found similar results.

"It's possible that this gene variant also protects against the development of Alzheimer's disease," said study author Nir Barzilai, MD, the director of the Institute for Aging Research at Albert Einstein College of Medicine in Bronx, NY.

Work is underway to develop a drug that emulates the effect of this life-extending version of the CETP gene. But I'd much rather get a gene therapy that'd enhance my liver cells to express the genetic variant for CETP that slows aging.

I've long thought the liver a key target for slowing whole body aging because it regulates blood lipid, lipoprotein, and cholesterol levels. This CETP gene variant (called CETP VV) is likely just one of many genetic variations waiting to be found that are expressed in the liver and can raise life expectancy. Another example genetic variation with life extending capabilities is Apolipoprotein A-I Milano high density lipoprotein (Apo A-I Milano HDL for short) clears out artery plaque and would also be a very beneficial gene with which to enhance one's liver.

Since livers age and become cancerous what we need are genetically engineered youthful replacement livers. The maximum benefit way to extend one's life through liver genetic engineering would be to grow a youthful replacement liver that has beneficial genes added. We can not do this yet. But in 10 or 20 years we should be able to take some existing liver cells, select out cells that have the least amount of accumulated DNA aging damage, do gene therapy on those cells in culture, then grow the cells up into a replacement liver. Next swap out your aged liver for a genetically enhanced younger liver. Your blood lipids will get changed by the new liver to slow the aging of your brain and body.

Seniors who have the CETP VV genetic variant have higher odds of reaching 100 years lower odds of developing dementia.

Led by Dr. Nir Barzilai, director of the Institute for Aging Research at Einstein, the researchers examined 158 people of Ashkenazi (Eastern European) Jewish descent who were 95 or older. Compared with elderly subjects lacking the gene variant, those who possessed it were twice as likely to have good brain function based on a standard test of cognitive function.

Later the researchers validated their findings independently in a younger group of 124 Ashkenazi Jews between the ages of 75 and 85 who were enrolled in the Einstein Aging Study led by Dr. Richard Lipton. Within this group, those who did not develop dementia at follow up were five times more likely to have the favorable genotype than those who developed dementia.

Dr. Barzilai and his colleagues had previously shown that this gene variant helps people live exceptionally long lives and apparently can be passed from one generation to the next. Known as CETP VV, the gene variant alters the Cholesterol Ester Protein. This protein affects the size of “good” HDL and “bad” LDL cholesterol, which are packaged into lipoprotein particles. Centenarians were three times likelier to possess CETP VV compared with a control group representative of the general population and also had significantly larger HDL and LDL lipoproteins than people in the control group.

People with the CETP VV variant had more HDL cholesterol and bigger particles in their blood.

The genetic variation causes people to produce less of a protein called cholesterol ester transfer protein (CETP). Barzilai says that CETP has two functions: it helps move cholesterol from the arteries to the liver, and it helps control the size of cholesterol particles circulating in the blood. People with the protective gene variant have higher levels of "good" HDL cholesterol and also produce bigger cholesterol particles, which scientists believe may not stick to blood-vessel walls as easily as small particles do.

CETP is on one of the 3 pathways that transfer cholesterol from HDL particles in the blood into the liver. So CETP is involved in regulating the amount of cholesterol in the blood.

Plasma high density lipoprotein (HDL) levels show an inverse relationship to atherogenesis, in part reflecting the role of HDL in mediating reverse cholesterol transport. The transfer of HDL cholesterol to the liver involves 3 catabolic pathways: the indirect, cholesteryl ester transfer protein (CETP)–mediated pathway, the selective uptake (scavenger receptor BI) pathway, and a particulate HDL uptake pathway. The functions of the lipid transfer proteins (CETP and phospholipid transfer protein) in HDL metabolism have been elucidated by genetic approaches in humans and mice. Human CETP deficiency is associated with increased HDL levels but appears to increase coronary artery disease risk.

Each tweak on genes causes many effects. CETP modification might or might not be the most effective way to improve blood lipids and slow brain and body aging. We might eventually find that CETP VV has side effects that are undesirable and that ApoA-I Milano will accomplish the same beneficial effects without some undesirable side effects. Or we might find CETP VV is better than ApoA-I Milano or some other genetic variants not yet discovered are better than either of them. Or maybe ApoA-I Milano and CETP VV work together synergistically to slow aging even more.

In mice genetically engineered to contain a human form of CETP a high fat high cholesterol diet turned up production of liver CETP from the CETP gene.

In three lines of transgenic mice the tissues expressing the human CETP mRNA were similar to those in humans (liver, spleen, small intestine, kidney, and adipose tissue); in two lines expression was more restricted. There was a marked (4-10-fold) induction of liver CETP mRNA in response to a high fat, high cholesterol diet. The increase in hepatic CETP mRNA was accompanied by a fivefold increase in transcription rate of the CETP transgene, and a 2.5-fold increase in plasma CETP mass and activity.

Brain rejuvenation is going to be the hardest rejuvenation task to accomplish. Anything that slows down brain aging is doubly beneficial. First off, your brain will function at a higher level longer during your working career and into retirement. That makes for better success at work and a happier life all around. Also, since the brain is going to be the hardest organ to rejuvenate we need to preserve it longer while we wait for effective brain rejuvenation biotechnologies.

More generally, while we desperately need therapies that do repair and replacement of aged parts we should not ignore the benefits and potential of slowing the aging process. Liver genetic engineering as an approach to slow the aging process is appealing because it looks much easier to do than full body gene therapy. If liver genetic engineering could buy us one or two decades of additional life that might be just the time we need to live long enough to still be alive when full body rejuvenation becomes possible.

By Randall Parker    2006 December 29 12:06 PM   Entry Permalink | Comments (7)
2006 January 05 Thursday
Genetic Risk For Alzheimers Causes Brain Insulation Decay

Genetic variations that contribute to risk of Alzheimer's also cause brain nerve insulation to decay.

A new UCLA imaging study shows that age-related breakdown of myelin, the fatty insulation coating the brain's internal wiring, correlates strongly with the presence of a key genetic risk factor for Alzheimer disease.

The findings are detailed in the January edition of the peer-reviewed journal Archives of General Psychiatry and add to a growing body of evidence that myelin breakdown is a key contributor to the onset of Alzheimer disease later in life.

In addition, the study demonstrates how genetic testing coupled with non-invasive evaluation of myelin breakdown through magnetic resonance imaging (MRI) may prove useful in assessing treatments for preventing the disease.

The idea of losing the insulation of the nerves of one's brain with aging strikes me as thoroughly disgusting. We should heavily fund attempts to develop treatments to prevent and reverse brain aging.

A genetic variation in Apolipoprotein E causes the myelin insulating sheaths to break down more rapidly with age.

As the brain continues to develop in adulthood and as myelin is produced in greater and greater quantities, cholesterol levels in the brain increase and eventually promote the production of a toxic protein that attacks the brain. The protein attacks myelin, disrupts message transfer through the axons and eventually can lead to the brain/mind-destroying plaques and tangles visible years later in the cortex of Alzheimer patients.

The Apolipoprotein E (ApoE) genotype is the second most influential Alzheimer risk factor, after only advanced age. The study used MRI to assess myelin breakdown in 104 healthy individuals between ages 55 and 75 and determine whether the shift in the age at onset of Alzheimer disease caused by the ApoE genotype is associated with age-related myelin breakdown.

The results show that in later-myelinating regions of the brain, the severity and rate of myelin breakdown in healthy older individuals is associated with ApoE status. Thus both age, the most important risk factor for Alzheimer disease, and ApoE status, the second-most important risk factor, seem to act through the process of myelin breakdown.

Some people argue that aging is a natural process or a sacred process which we can experience with dignity. But where's the dignity of suffering from a progressive breakdown of the insulation on the nerves of your brain? One doesn't just become gray and wrinkly and move more slowly with age. One's brain goes. One loses the ability to think as well. One is more prone to confusion, less able to deal with the problems of life, less able to recall memories of past events or to remember what one has to accomplish on any given day. There's nothing the least bit dignified about brain decay. It does not bring wisdom. It takes away the ability to recall lessons learned.

By Randall Parker    2006 January 05 10:46 PM   Entry Permalink | Comments (5)
2006 January 01 Sunday
Genetic Regions Involved In Brain Aging Rates Identified

Really old folks have genetic variations that help keep their brains humming.

A study released today at the American College of Neuropsychopharmacology's Annual Meeting revealed that scientists have identified genes related to reaching age 90 with preserved cognition. The study, which was funded by the National Institutes of Health and conducted at the University of Pittsburgh, is among the first to identify genetic links to cognitive longevity.

"While successful aging has been defined in many ways, we focused on individuals who had reached at least 90 without significant decline in mental capacity," said lead researcher George S. Zubenko, MD, PhD, Professor of Psychiatry and Biological Sciences at the University of Pittsburgh School of Medicine. "Not only is this a goal that many of us share, this definition of 'successful aging' can be determined objectively and consistently across subjects--an important requirement of scientific studies."

While previous research found that genes make important contributions to exceptional longevity, the goal of this study was to identify regions of the human genome that contributed, along with lifestyle factors, to reaching age 90 with preserved cognition.

The study involved 100 people age 90 and older with preserved cognition, as measured by clinical and psychometric assessments. Half of the subjects were male, half were female. Using a novel genome survey method, scientists compared the DNA of the study sample with that of 100 young adults, aged 18-25 years old, who were matched for sex, race, ethnicity and geographic location. Specifically, Dr. Zubenko and his research team attempted to identify specific genetic sequences present in older individuals that may be linked to reaching older ages with preserved cognitive abilities, or conversely, specific genetic sequences present in younger individuals (and not present in those over age 90) that may impede successful aging. The study also looked at a variety of lifestyle factors, such as smoking and alcohol consumption, with the goal of eventually exploring the interactive effects of genes and lifestyle on successful aging.

As expected, the study identified an increased frequency of the APOE E2 allele and a decreased frequency of the APOE E4 allele among the elders compared to the group of young adults. These gene variants confer protection and risk, respectively, of Alzheimer's disease, the most common cause of dementia in late life. The study also identified novel genetic regions associated with successful aging, including DYS389 and DYS390, some of which affected men or women, but not both.

The problem for us is that we already have our versions of genes in our brains. Also, gene therapy is very hard to do and especially hard to do in the brain. However, identification of specific genes that influence aging rate leads to the investigation of mechanisms by which some variants slow or accelerate aging.

Genes that influence brain aging are especially important. Probably in 20 or 30 years time we will be able to grow replacements for all the internal organs. Old parts will be replaced with new parts. But the brain is our identity and needs to be repaired, not replaced. Preferably individual neurons should even be repaired rather than replaced. This makes brain rejuvenation much harder than rejuvenation of the rest of the body. We need to slow brain aging because effective rejuvenation therapies for the brain are going to take longer to develop than rejuvenation therapies for the rest of the body. Also, brain aging has a big economic impact long before we die. Declines in intellectual ability translate into declines in job performance and income.

Even if you are very confident that a cure for aging will be found before you die that is not a reason to be complacent about your diet and lifestyle. Your brain will age and your cognitive abilities will decline while we wait for the realisation of Strategies for Engineered Negligible Senescence (SENS) therapies. Also, a lot of afflictions of middle age and later are no fun at all. Best to delay the onset of assorted maladies as long as you can.

By Randall Parker    2006 January 01 06:51 PM   Entry Permalink | Comments (1)
2004 June 11 Friday
Gene Expression Shows Human Brains Age At Different Speeds

Brain genes for learning, stress, repair, inflammation, and immune responses all showed altered responses as we age.

To investigate age-associated molecular changes in the human brain, Dr. Bruce A. Yankner, professor in the Department of Neurology and Division of Neuroscience at Children's Hospital Boston and Harvard Medical School, and colleagues examined patterns of gene expression in postmortem samples collected from thirty individuals ranging in age from 26 to 106 years. Using a sophisticated screening technique called transcriptional profiling that evaluates thousands of genes at a time, the researchers identified two groups of genes with significantly altered expression levels in the brains of older individuals. A gene's expression level is an indicator of whether or not the gene is functioning properly.

"We found that genes that play a role in learning and memory were among those most significantly reduced in the aging human cortex," said Yankner. "These include genes that are required for communication between neurons."

In addition to a reduction in genes important for cognitive function, there was an elevated expression of genes that are associated with stress and repair mechanisms and genes linked to inflammation and immune responses. This is evidence that pathological events may be occurring in the aging brain, possibly related to gene damage.

The researchers then went on to show that many of the genes with altered expression in the brain were badly damaged and could not function properly. They showed that these genes also could be selectively damaged in brain cells grown in the laboratory, thereby mimicking some of the changes of the aging brain.

"Our findings suggest that these genes are unusually vulnerable to damage from agents such as free radicals and toxins in the environment," said Yankner. "The brain's ability to cope with these toxic insults and repair these genes declines with age, leading to their reduced expression. It will now be important to learn how to prevent this damage, and to understand precisely how it impacts brain function in the elderly."

According to Yankner, "If you examine brain gene patterns among young adults, they are quite similar. In very old adults, there is some increased variability, but there is still similarity between individuals. In contrast, individuals in the middle age population between 40 and 70 years of age are much more variable. Some middle-aged individuals exhibit gene patterns that look more like the young group, whereas others show gene patterns that look more like the old group."

This is evidence that people may age differently during middle age. It will now be of great interest to understand what it is that makes some people age more rapidly than others.

These findings raise the exciting possibility that treatments or lifestyles that reduce gene damage in young adults may delay cognitive decline and the onset of brain diseases in later years. However, more research is needed.

"We can repair these aging genes in the laboratory, but that is a far cry from the human brain. This is only a first step," cautions Yankner.

The brain is going to be the hardest organ to repair and rejuvenate. With most organs we are going to be able to just grow replacements or at least replace pieces. But each of your neurons involved in memory or personality encode a part of who you are. Killing off old neurons kills off some small part of who you are. We need to be able to repair individual aged cells. That is going to be hard to do.

The hardest problem is going to be the development of gene therapy techniques for delivering genes into brain cells. The removal of extracellular accumlated junk is probably a more solvable problem as vaccines have already showed considerable promise in removing the beta amyloid plaques involved in Alzheimer's Disease. It is possible that the removal of at least some of the intracellular junk may not turn out to require gene therapy. But my guess is that part of the intracellular junk that accumulates in lysosomes will require gene therapies developed to provide enzymes that can break down that junk.

We need much greater funding and effort aimed at developing brain rejuvenation therapies. We also need a lot more research aimed at discovering why some brains age more rapidly than others. However, it is very likely that just improving blood lipid and cholesterol profiles will reduce the oxidative load on the brain and therefore reduce the rate of brain aging. The sorts of dietary and exercise advice aimed at avoiding heart disease and cancer will very likely slow brain aging as well.

If this report of middle aged signs of brain aging makes the problem more real to you and makes you feel you ought to do something to protect your brain then consider the "ape" diet to improve blood lipids and cholesterol. The ape diet uses a combination of nuts, foods high in soluble fiber (e.g. eggplant), margarines fortified with plant sterols, soy, and vegetables. The ape diet lowers cholesterol, C Reactive Protein (an inflammation indicator), and triglycerides.

There is now a large accumulation of studies which show that cholesterol-lowering statin drugs reduce the risk of Alzheimer's Disease and vascular dementia. Though be aware that some statin drug users experience acute memory problems. Still, you can always stop taking a statin drug or switch to a different one if you experience harmful cognitive effects. But if you are not going to take statins then for the sake of your brain at least consider being like an ape man when you eat and lower your cholesterol that way. Ray Davies had it all figured out years ago when he sang "I'm an ape man, I'm an ape ape man, oh I'm an ape man. I'm a King Kong man, I'm a voodoo man, oh I'm an ape man".

Also see my previous posts Brain Aging Studied With Gene Microarrays, Myelin Cholesterol and Iron Build-Up Leads To Alzheimer's, GABA Neurotransmitter Rejuvenated Aged Monkey Brains, Vitamin C, E In High Dose Combination May Protect Against Alzheimer's.

By Randall Parker    2004 June 11 03:09 PM   Entry Permalink | Comments (1)
Site Traffic Info