FGF21: Learning to Live Longer from Starving Mice

Biologists have known for several decades that putting mice on a starvation diet leads the mice to live longer -- although not necessarily happier. Humans derive too much pleasure from food to broadly adopt this approach to a longer life, but there may be easier ways to get the same benefit.

In 1934, in a famous experiment at Cornell University, it was discovered that laboratory mice could live twice as long as expected if they were fed a low-calorie diet that included enough nutrients to avoid malnutrition. This phenomenon has since been observed in species ranging from worms to primates, but not in humans. Reducing calorie intake leads to longer lives by modifying a number of the biochemical pathways that sense nutrients, including pathways that involve insulin and various other biomolecules. Chemical and genetic methods can also increase longevity by modifying these pathways, which suggests that it might be possible to develop drugs that can increase lifespan without the reducing calorie intake. _Bioscholar News

"In our study, we found transgenic mice that produced more of the hormone fibroblast growth factor-21 (FGF21) got the benefits of dieting without having to limit their food intake," says professor Steven Kliewer of UT Southwestern Medical Center. "Male mice that overproduced the hormone had about a 30 percent increase in average life span and female mice had about a 40 percent increase in average life span." When it comes to maximum life expectancy, the data isn't even all in yet: while none of the untreated mice lived longer than about three years, some of the female mice that overproduced FGF21 will soon reach the age of four. _TGDaily

If the life extension benefits from mice were to transfer to humans, men would live over 20 years longer with more FGF21, and women would live over 30 years longer. And they would be able to eat a normal diet, without starving themselves.

FGF21 is only a part of a complex network of proteins and hormones that affect metabolism and growth. But it appears to be a central part of the network, which may work as a key to unlock some important doors of understanding of metabolic diseases such as diabetes mellitus type 2, mechanisms of growth, as well as providing insights into the ageing process and diseases of ageing.

Fibroblast growth factor-21 (FGF21) is a hormone secreted by the liver during fasting that elicits diverse aspects of the adaptive starvation response. Among its effects, FGF21 induces hepatic fatty acid oxidation and ketogenesis, increases insulin sensitivity, blocks somatic growth and causes bone loss. Here we show that transgenic overexpression of FGF21 markedly extends lifespan in mice without reducing food intake or affecting markers of NAD+ metabolism or AMP kinase and mTOR signaling. Transcriptomic analysis suggests that FGF21 acts primarily by blunting the growth hormone/insulin-like growth factor-1 signaling pathway in liver. These findings raise the possibility that FGF21 can be used to extend lifespan in other species. _eLife

There are too many unanswered questions regarding the entire tapestry of hormones involved in growth, metabolism, and ageing, for scientists to recommend use of FGF21 in humans.

The relationship of FGF21 to diabetes and bone density must be teased out and better defined. An intriguing relationship between FGF21 and hibernation should also be better illuminated and clarified.

FGF21 is certainly not THE answer to ageing. But it is very likely to lead us to a number of better questions. And eventually, it may add a decade or two of healthy lifespan to people of the near future.

AUF1 Hat Trick: Suppresses Inflammation, Reduces Cancer Risk, and Inhibits Cellular Senescence

Researchers at NYU School of Medicine have, for the first time, identified a single gene that simultaneously controls inflammation, accelerated aging and cancer. _NYU SOM

AUF1 is a micro-RNA binding protein that has been found to perform multiple vital cell functions. Engineered mice that lack the AUF1 protein suffer rapid premature aging that worsens with each generation. By replacing AUF1 function in these mice, the harmful premature aging and accelerated cellular senescense can be reversed.

AUF1 binds and strongly activates the transcription promoter for telomerase catalytic subunit Tert. In addition to directing inflammatory cytokine mRNA decay, AUF1 destabilizes cell-cycle checkpoint mRNAs, preventing cellular senescence. Thus, a single gene, AUF1, links maintenance of telomere length and normal aging to attenuation of inflammatory cytokine expression and inhibition of cellular senescence. _Molecular Cell (ScienceDirect)

AUF1 also accelerates the degradation of inflammatory cytokine, reducing the inflammation load on cells and tissues. More from NYU School of Medicine, where much of the recent research on AUF1 was done:

For decades, the scientific community has known that inflammation, accelerated aging and cancer are somehow intertwined, but the connection between them has remained largely a mystery, Dr. Schneider said. What was known, due in part to past studies by Schneider and his team, was that a gene called AUF1 controls inflammation by turning off the inflammatory response to stop the onset of septic shock. But this finding, while significant, did not explain a connection to accelerated aging and cancer.

When the researchers deleted the AUF1 gene, accelerated aging occurred, so they continued to focus their research efforts on the gene. Now, more than a decade in the making, the mystery surrounding the connection between inflammation, advanced aging and cancer is finally being unraveled.

The current study reveals that AUF1, a family of four related genes, not only controls the inflammatory response, but also maintains the integrity of chromosomes by activating the enzyme telomerase to repair the ends of chromosomes, thereby simultaneously reducing inflammation, preventing rapid aging and the development of cancer, Dr. Schneider explained.

“AUF1 is a medical and scientific trinity,” Dr. Schneider said. “Nature has designed a way to simultaneously turn off harmful inflammation and repair our chromosomes, thereby suppressing aging at the cellular level and in the whole animal.”

With this new information, Dr. Schneider and colleagues are examining human populations for specific types of genetic alterations in the AUF1 gene that are associated with the co-development of certain immune diseases, increased rates of aging and higher cancer incidence in individuals to determine exactly how the alterations manifest and present themselves clinically. _NYU

This is an exciting and potentially important finding. But it takes time for exciting research discoveries to be converted into potentially revolutionary therapies against cancer, aging, and crippling inflammatory diseases.

Early attempts to capitalise on this discovery are likely to be disappointing, particularly as expectations will tend to be raised prematurely. But as the ability to generate safe, effective, affordable treatments begins to catch up to the ability to discover the mechanisms of biological function at multiple levels, the pace of change may grow at a startling rate.

The important thing is to get the basic science findings into the hands of the research community for replication, clarification, and elaboration. After that, scientists can begin finding ways to make the research work in favour of an abundant human future.

Original 1997 identification of AUF1 at Rutgers and Wake Forest (PDF)

H/T Nextbigfuture

Two Hints of the Possibility for a Healthy Long Life

The first hint comes from the Mayo Clinic's Darren Baker. Baker has developed a way of delaying symptoms of old age in mice, and has even been able to reverse some signs of aging in already aged mice. Here's more:

Baker has developed a way of killing all of a mouse’s senescent cells by feeding them with a specific drug. When he did that in middle age, he gave the mice many more healthy years. He delayed the arrival of cataracts in their eyes, put off the weakening of their muscles, and held back the loss of their body fat. He even managed to reverse some of these problems by removing senescent cells from mice that had already grown old. There is a lot of work to do before these results could be applied to humans, but for now, Baker has shown that senescent cells are important players in the ageing process.

Note that the mice in this study didn’t live any longer; they just spent more of their life being healthy.

Baker exploited the fact that many senescent cells rely on a protein called p16-Ink4a. He created a genetic circuit that reacts to the presence of p16-Ink4a by manufacturing an executioner: a protein called caspase-8 that kills its host cell. Caspase-8 is like a pair of scissors – it comes in two halves that only work when they unite. Baker could link the two halves together using a specific drug. By sneaking the drug into a mouse’s food, he activated the executioners, which only killed off the cells that have lots of p16-Ink4a. Only the senescent ones get the chop.

Baker tested out this system in a special strain of genetically engineered mice that age very quickly. It worked. The senescent cells disappeared, and that substantially delayed the onset of muscle loss, cataracts, and fat loss. Typically, around half of these mice show signs of muscle loss by five months of age. Without their senescent cells, only a quarter of them showed the same signs at ten months. Their muscle fibres were larger, and they ran further on treadmills. Even old mice, whose bodies had started to decline, showed improvements. _Discover

Another look at this research from the Economist:

Dr Baker genetically engineered a group of mice that were already quite unusual. They had a condition called progeria, meaning that they aged much more rapidly than normal mice. (A few unfortunate humans suffer from a similar condition.) The extra tweak he added to the DNA of these mice was a way of killing cells that produce P16INK4A. He did this by inserting into the animals’ DNA, near the gene for P16INK4A, a second gene that was, because of this proximity, controlled by the same genetic switch. This second gene, activated whenever the gene for P16INK4A was active, produced a protein that was harmless in itself, but which could be made deadly by the presence of a particular drug. Giving a mouse this drug, then, would kill cells which had reached their Hayflick limits while leaving other cells untouched. Dr Baker raised his mice, administered the drug, and watched.

The results were spectacular. Mice given the drug every three days from birth suffered far less age-related body-wasting than those which were not. They lost less fatty tissue. Their muscles remained plump (and effective, too, according to treadmill tests). And they did not suffer cataracts of the eye. They did, though, continue to experience age-related problems in tissues that do not produce P16INK4A as they get old. In particular, their hearts and blood vessels aged normally (or, rather, what passes for normally in mice with progeria). For that reason, since heart failure is the main cause of death in such mice, their lifespans were not extended.

The drug, Dr Baker found, produced some benefit even if it was administered to a mouse only later in life. Though it could not clear cataracts that had already formed, it partly reversed muscle-wasting and fatty-tissue loss. Such mice were thus healthier than their untreated confrères. _Economist

This research will require replication and a great deal of clarification, before it moves from mice to larger mammals such as humans. But it opens up a number of possible avenues of research.

The second hint of likely means to achieve healthier long lives, is research done in fruit flies at the Salk Institute, in southern California.

Although it is a well-documented fact that restricting calories during daily food intake is the easiest strategy to extend life spans for both humans and animals, little is known about biological mechanisms underlying this phenomenon.

..."Fruit flies and humans have a lot more in common than most people think," said Leanne Jones, an Associate Professor at Salk's Laboratory of Genetics and a lead scientist on the project, "There is a tremendous amount of similarity between a human small intestine and the fruit fly intestine."

The researchers found that boosting the activity of dPGC-1, the Fruit Fly version of the gene, resulted in greater numbers of mitochondria and more energy-production in flies; the same phenomenon is seen in organisms on calorie restricted diets.

When the activity of the gene was accelerated in stem and progenitor cells of the intestine, which serve to replenish intestinal tissues, these cellular changes correspond with better health and longer lifespan.

The flies lived between 20 and 50 percent longer, depending on the method and extent to which the activity of the gene was altered. _ibtimes

The fruit fly research suggests that not only healthier long lives are possible, but "longer long" lives are possible as well.

The approach taken by the SENS Foundation involves using multiple approaches to extending healthy lifespan. Destroying senescent cells -- such as Darren Baker is learning to do -- is one of the main approaches that SENS is following. Improving the function of mitochondria is another of the main tactics of SENS.

As humans in advanced societies are putting less and less energy into raising children, and putting more and more energy into raising themselves, thoughts of increased longevity and lifespan are coming more into the mainstream of respectability. The main limitation to further research into life extension is -- as always -- funding. But even with unlimited funding, moving the research from animal models into human therapeutics would take a matter of decades.

Can Delaying Puberty & Extending Childhood Increase Lifespan?

Puberty seems to be arriving at earlier ages for both boys and girls. There are many reasons why puberty onset is earlier now, but most of these reasons are still unclear. The problems that arise from premature puberty include violence, higher risks of cancer and diabetes, increased behavioural problems (drugs, alcohol, delinquency etc), isolation from peer groups -- even a change in growth rates for the children of girls with premature onset of puberty.

ImageSource

...children who go into early puberty are prematurely sexualised and too immature to deal with the implications. They are more vulnerable to sexual abuse, inappropriate sexual behaviour, sexually transmitted diseases and teenage pregnancy. “It means that children develop sexually much earlier,” Stanhope says. “They are physically ready for sexual reproduction but mentally completely unready.”

Studies have shown that adolescents who go through puberty earlier are involved in more risk-taking behaviour, such as taking drugs, binge drinking and breaking the law. A premature increase in testosterone can lead to aggression in boys who lack the maturity to control impulses. “We all realise that testosterone is a very difficult hormone to learn to live with,” Stanhope says, tapping a pencil vigorously on his pockmarked table, “and if you get a rise in testosterone outside the normal physiological age, then it’s even more of a problem.”

Research published this year in the Australian and New Zealand Journal of Criminology also found increased aggression in girls who reached puberty early. In Britain the uncomfortable reality that children are becoming sexually mature earlier has been overlooked in the recent debate about the over-sexualisation of children. Instead of simply focusing on cynical manufacturers producing padded bras for seven-year-olds, perhaps we should also consider how to respond to the new reality that some girls are now growing breasts at this age.

Stanhope also points out that for women there may be long-term health problems, because early puberty increases exposure to oestrogen. According to Cancer Research UK, a girl who has her first period a year later than her contemporaries has 5% less risk of developing breast cancer in later life. “There may be an important link with breast and ovarian cancer,” Stanhope says. “The earlier a girl has her period, the longer her exposure to oestrogen and this may well have very important sequelae for oestrogen-dependent tumours. This increases her risk of breast cancer, ovarian cancer and of developing cardiovascular problems.”

Girls who reach puberty early are also more likely to develop type 2 diabetes. A 37-year-long study of 61,000 Norwegian women showed that women who got their first period at ten or 11 had a 10% higher mortality rate than those who got their period four years later. _PubertyBlues

Scientists are beginning to home in on the physiological initiators of puberty, and have found a way to delay puberty in mice. By "knocking out" a specific gene, IGF-1R, researchers have both delayed puberty and maintained normal reproductive function after puberty in these knockout mice.

Pubertal onset, initiated by pulsatile gonadotropin-releasing hormone (GnRH), only occurs in a favorable, anabolic hormonal milieu. Anabolic factors that may signal nutritional status to the hypothalamus include the growth factors insulin and IGF-1. It is unclear which hypothalamic neuronal subpopulation these factors affect to ultimately regulate GnRH neuron function in puberty and reproduction. We examined the direct role of the GnRH neuron in growth factor regulation of reproduction using the Cre/lox system. Mice with the IR or IGF-1R deleted specifically in GnRH neurons were generated. Male and female mice with the IR deleted in GnRH neurons displayed normal pubertal timing and fertility, but male and female mice with the IGF-1R deleted in GnRH neurons experienced delayed pubertal development with normal fertility. With IGF-1 administration, puberty was advanced in control females, but not in females with the IGF-1R deleted in GnRH neurons, in control males, or in knockout males. These mice exhibited developmental differences in GnRH neuronal morphology but normal number and distribution of neurons. These studies define the role of IGF-1R signaling in the coordination of somatic development with reproductive maturation and provide insight into the mechanisms regulating pubertal timing in anabolic states. _JCI

Scientists will find additional triggers for pubertal onset besides insulin and IGF-1, and some of those factors may provide a more benign approach to the delaying of puberty.

Paradoxically, IGF-1 is vital for normal development of mice, but knocking out IGF-1 receptors in certain flies and worms can increase lifespan. That paradox is still being studied.

So -- how long should puberty be delayed, if at all? If childhood could be extended for several more years without impairing the ability of the child to learn and mature psychologically, would the potential health and societal benefits be worth the postponement of sexual development of the child?

What if aging itself were to be postponed along with puberty? If total lifespan were extended by the number of extra years a person spent in childhood, would that be beneficial to society or not? What if a person could live an extra 20, 30, or 50 years -- but had to spend those extra years as a pre-pubertal child. Would it be worth it?

Those who see increased longevity as a sure path to overpopulation collapse of Earth's ecosystem, would insist upon some form of sterilisation for those who opt for longevity. In some countries, laws of that type -- mandating permanent sterilisation for anyone undergoing longevity treatments -- should be expected.

Extended pre-puberty is a form of time-limited and (probably) reversible sterilisation, so any longevity approach that also delayed puberty significantly, should not raise the hackles of those suffering from overpopulation anxiety too much. But there are likely to be a large number of objections to such treatments, all the same.

Modern societies appear to see children in a schizoid manner. Fewer children are born, so the one or two children a family does have, are cherished and pampered. On the other hand, children are seen as a hindrance to a hedonic lifestyle, an exorbitant expense and often a great bother. Overall, most children do not seem to be raised or educated very well in modern societies, judging by observable results.

While childhood is not prolonged in modern societies, an incompetent adolescence is certainly prolonged -- in many cases indefinitely. Given the choice between a prolonged childhood leading into an accelerated but prepared-for adolescence, and the current state of lifelong incompetent adolescence commonly seen in the affluent world, most Al Fin mental health professionals would choose the prolonged childhood combined with a prepared-for adolescence that leads into a responsible and competent adulthood.

Previously published at Al Fin

50 Best Anti-Ageing Blogs

The Ultrasound Technician Schools blog has put together a list of the 50 top anti-ageing blogs, for those who want to follow the broad range of online approaches to ageing and longevity.

Some of Al Fin's favourites that are on the list include Fight Aging, Ouroboros, and the Alliance for Aging Research.

Al Fin Longevity -- this blog -- finds itself on the top 50 list under the category of Longevity and Life Extension at #43.

As a side topic, I have noticed several healthcare training related blogs that provide wide ranges of lists of blogs for various topics. Some of these lists are quite useful. In fact, I would like to see a list of the top 100 list-making blogs. Wait -- what about a top 100 list of lists of top 100 list-making blogs? How about ..... Thwack!!

All righty then. My domestic android, Valerie, has just slapped me to bring me out of my list fugue. As Valerie points out, by the time you compiled the ultimate top 100 list of top 100 lists of lists of top 100 list-making blogs, the entire list would probably be obsolete. Please pardon me for the regression.

As scientific research pushes on, an extended lifespan becomes much more likely. The challenge will be not so much to keep living, but to combine the optimum mixture of enjoyable and important activities in order to fill one's life satisfactorily.

More important than improving the quantity of life is improving the quality of life. But doing both at the same time beats either one alone.

Universal Aging Mechanism?

As an organism changes, its pattern of gene activation/deactivation and repair changes from a vibrant youthful pattern to a less efficient and effective senescent pattern. Harvard scientists are learning more about some of the underlying mechanisms behind this "genetic control shift of aging."

The researchers found in studies of mammalian stem cells that the protein SIRT1 controls the packaging of DNA into chromatin, thereby setting the youthful pattern of gene activity by keeping select genes switched off. In response to DNA damage, those SIRT1 proteins leave their posts to go off and assist in the necessary repairs. That change in SIRT1's job description leads to shifts in gene activity that parallel those seen in the aging mouse brain, they show. They suspect similar changes would also be found in other body tissues as well.

" The critical protein controls both which genes are off and on as well as DNA repair; it's used for both processes, and that's the catch," said David Sinclair of Harvard Medical School. "As cells accumulate DNA damage, the protein can't do both jobs sufficiently." Once SIRT1 loses control, gene activity goes haywire, a state of affairs that leads to symptoms associated with aging.

Sinclair's team also found what they consider to be good evidence that the aging process can be slowed. Mice with an excess of SIRT1 had an improved ability to repair DNA and prevent those unwanted changes in gene expression. The hope is that those improvements could be reproduced with a drug that stimulates SIRT1, they said. _Eurekalert

Permanent gene therapy to boost SIRT1 for both gene repair and maintaining a youthful gene activity pattern seems preferable to a daily pill or injection. In fact, genetic therapy will likely replace most pharmaceuticals as we learn more about the underlying physiology and pathology of our organisms. SIRT1 will be but a small part of the overall story of aging. But for now, it appears to be an important early step in our understanding.

Aging Biomarkers plus Importance of Lysosomes

Researchers are looking for biomarkers which would reveal the state of aging in an organism. Given the relationship between telomere length and cell reproductive capacity, researchers at Rockefeller University looked for biomarkers of telomere shortening.

Telomere dysfunction limits the proliferative capacity of human cells by activation of DNA damage responses, inducing senescence or apoptosis. In humans, telomere shortening occurs in the vast majority of tissues during aging, and telomere shortening is accelerated in chronic diseases that increase the rate of cell turnover. Yet, the functional role of telomere dysfunction and DNA damage in human aging and diseases remains under debate. Here, we identified marker proteins (i.e., CRAMP, stathmin, EF-1α, and chitinase) that are secreted from telomere-dysfunctional bone-marrow cells of late generation telomerase knockout mice (G4mTerc−/−). The expression levels of these proteins increase in blood and in various tissues of aging G4mTerc−/− mice but not in aging mice with long telomere reserves. _PNAS_via_NBF

It will be interesting to determine if the same markers are present in humans.

Scientists at Albert Einstein College of Medicine have managed to "stop the aging process" by boosting cellular protein clearance.

"Many of these diseases [of aging AF] are due to 'misbehaving' or damaged proteins that accumulate in neurons. By preventing this decline in protein clearance, we may be able to keep these people free of symptoms for a longer time."

If the body's ability to dispose of cell debris within the cell were enhanced across a wider range of tissues, she says, it could extend life as well.

In healthy organisms, a surveillance system inside cells called chaperone-mediated autophagy (CMA) locates, digests and destroys damaged proteins...Specialised molecules, the "chaperones", ferry the harmful material to membrane-bound sacs of enzymes within the cells known as lysosomes...Once the cargo has been "docked", a receptor molecule transfers the protein into the sac, where it is rapidly digested.

With age, these receptors stop working as well, resulting in a dangerous build-up of faulty proteins that has been linked, in the liver, to insulin resistance as well as the inability to metabolise sugar, fats or alcohol.

The same breakdown of the cell's cleaning machinery can also impair the liver's ability to remove the toxic build-up of drugs at a stage in life when medication is often part of daily diet.

In genetically modified mice, Cuervo compensated for the loss of the receptors in the animals by adding extra copies...."That was enough to maintain a clean liver and to prove that if you keep your cells clean they work better," she says. _Source_via_NextBigFuture

Cleaning up cellular debris buildup is part of Aubrey de Grey's SENS program of engineered anti-senescence.

Anti-aging research proceeds along several fronts. It is important to be able to monitor a person's state of aging, if anti-aging therapy is to be put upon a sound scientific basis. And it is vital to produce many safe and effective therapies against as wide a range of aging mechanisms as possible.

Aging 2008 at UCLA

The Methuselah Foundation announces "Aging2008" at UCLA Friday June 27th.

The speakers at Aging 2008 will argue that the near-term consequences of intense research into regenerative medicine could be the development of therapies that extend healthy human life by decades, even if the therapies are applied in middle age. Peter Thiel, president of Clarium Capital, initial investor in Facebook, and lead sponsor of Aging 2008, said, "The time has come to challenge the inevitability of aging. This forum will provide an excellent opportunity to look at the scientific barriers that must be overcome to substantially extend healthy human life, as well as the sociological implications of doing so."

Aging 2008 also serves as the free opening session for the technically focused Understanding Aging Conference, which will run at UCLA on June 28th and 29th.

What: Aging: The Disease, The Cure, The Implications, hosted by Methuselah Foundation

When: Friday, June 27, 2008, Drinks 4pm, Presentations 5pm, Dinner 8pm

Where: Royce Hall, 405 Hilgard Ave, Los Angeles, CA 90024 __Source

Phase I Trials: Prodarsan for Cockayne's Syndrome

Prodarsan is a combination of small protein molecules devised by Pharming NV[PHGUF.PK] for treatment of premature aging including Cockayne's Syndrome.

Leiden, The Netherlands, April 23, 2008. Biotech company Pharming Group NV (Pharming) (NYSE Euronext: PHARM) announced today that its wholly owned subsidiary DNage has started a Phase I clinical study to evaluate the pharmacokinetics and tolerability of Prodarsan(R) in humans.

Premature ageing, the primary target of Prodarsan(R), is a group of rare genetic diseases which manifests itself in several forms that are genetically and clinically similar although not identical. Dependent on the specific form of the disease, patients have a strongly reduced life expectancy and exhibit many ageing-related diseases early on in their lives. There is currently no effective therapy available for these patients.

Pharming has demonstrated that Prodarsan(R) as an oral, liquid formulation has significant effects in animal models for Cockayne Syndrome (CS). CS is one of the more common forms of premature ageing and is characterized, amongst others, by growth failure, mental retardation, eye abnormalities and a reduced life expectancy. The positive effects of Prodarsan(R) in preclinical testing on life expectancy in general and more specifically on the eye abnormalities are promising for further development of the product and its testing in humans.

The Phase I trial that is now being conducted consists of a combined single and multiple dose escalating clinical study in healthy volunteers. By studying the pharmacokinetics and tolerability of Prodarsan(R) and the effects of food intake on the absorption and elimination of the product, an oral dosing scheme will be determined that targets the pharmacological effective concentration range effectively. It is expected that following a successful completion of this trial the first clinical studies in patients will start later in 2008. Source

Prodarsan's proposed mechanism of action is via the DNA repair mechanism of the cell.

CKN1 is caused by a defect in the Cockayne syndrome type A gene (CSA or ERCC8) located on chromosome 5. Affected persons inherit 2 mutant genes, one from each parent. Cells carrying ERCC8 mutations are hypersensitive to UV light. They do not recover the ability to synthesize ribonucleic acid (RNA) after exposure to UV light. In addition, the cells cannot remove and degrade deoxyribonucleic acid (DNA) lesions from strands that have active transcription.

Mutations in the DNA excision repair gene ERCC6 located on band 10q11 cause CS type 2 (MIM number 133540; CSB). This gene encodes helicase, a protein that is presumed to have DNA unwinding function. Mutations include a deletion of exon 4, an amino acid substitution at the 106th glutamine to proline (Q106P) in the WD-40 repeat motif of the CSA protein, and large deletion in the upstream region, including exon 1 of the CSA gene. The Q106P mutation could alter the propeller structure of the CSA protein, which is important for the formation of the CSA protein complex. Additionally, a missense mutation (A205P) and a nonsense (E13X) mutation have been identified, as well as a new common single nucleotide polymorphism in CKN1. No genotype-phenotype correlation exists. _EMedicine

We can hope that experience in augmenting DNA repair in the tragic accelerated aging syndromes may be helpful in devising strategies to augment DNA repair in helping to delay normal aging.

Aubrey de Grey's Ending Aging

I recently had the opportunity to read Aubrey de Grey's briskly selling book, Ending Aging.

The book goes into more detail about the 7 approaches to anti-senescence discussed at the SENS website. Consider a progress report on a very important front of scientific research. Arnold Kling takes an economist's look at the book, and is intrigued:

Four years ago, I reported that de Grey foresees a not-too-distant future in which humans can reverse the effects of aging, raising the possibility of living healthy lives for hundreds of years. He has not backed away from that position, and this book, written by de Grey and his research associate Michael Rae, represents an update from his perspective. In brief, he says that

1. The latest scientific research indicates no flaws in the theory that aging can be eradicated.

2. However, getting the required techniques developed will require institutional changes relative to our current system for conducting medical research.

As an economist, I am most interested--and most qualified to form an opinion about--the second point.

...De Grey sees aging as a byproduct of an evolutionary process that takes place within the body. Mutations occur over time within your cells, sometimes randomly and sometimes stimulated by external events. This evolutionary process changes the balance between what I might call "good stuff" and "bad stuff" (here I am taking the technical caliber of the scientific exposition down several levels). Sometimes, the "good stuff" gets stronger, as when we develop an immunity to a disease. More often, however, the "good stuff" gets weaker and the "bad stuff" (like arterial plaque or pre-cancerous cells) gets stronger. It is this shift in the balance that leads to the symptoms of aging, including susceptibility to disease, which ultimately proves fatal.

Because aging is a natural outcome of the body's internal evolutionary processes, de Grey argues that the standard paradigm for fighting the diseases of aging one by one is flawed. Prevention of one disease, in the form of slowing the processes that cause it, is a doomed strategy.

...Too often, academics use their credentials to spit out biased polemics dressed up as science. Ending Aging is the opposite. It is a crash course in state-of-the-art science dressed up as a polemic. De Grey wears his passion for undertaking a war on aging on his sleeve, yet most of the book consists of scientific analysis that, although simplified to enable a layman to follow, is conscientious in reporting doubts and objections to the author's point of view.

...What de Grey is saying is that today's cautious approach to experimental medical testing significantly slows the rate of progress, which means that many people will suffer and die unnecessarily. However, those people are unseen and unknown, whereas those who suffer and die as a result of medical experiments are identifiable and visible. I think that trying to sell people on the idea of taking more risks in order to advance medical progress is not as straightforward as de Grey makes it sound

...My guess is that de Grey will have better luck if he tries to mobilize wealthy philanthropists. If instead of donating buildings to universities our billionaires would donate money for prizes that reward general-purpose medical technologies, we might not have to wait for government research to adopt a paradigm shift, which is almost surely not going to happen. Wealthy (and not-so-wealthy) philanthropists who are reading this should check out de Grey's organization SENS and look for ways to contribute both to his institute and to a prize fund.

TCS

Future research will make part of de Grey's program moot and unnecessary. Other future research will likely incorporate some of de Grey's ideas. The point is, de Grey's approach is the best one currently operating, so that if someone did have extra money he/she was thinking about donating to science, they could do much worse than to donate to SENS.

I recommend the book to anyone interested in the extension of healthy human lifespan. Getting much of the same information from the SENS website + literature searches is possible, but you wouldn't want to miss Aubrey's unique argumentative style.

More on Resveratrol

Scientists at Harvard and MIT have added to the "Resveratrol mystique." Their research adds weight to the Resveratrol::Sirt1 connection, and suggests that Resveratrol may be useful in preventing neurodegenerative diseases such as Alzheimer's.

The scientists have shown that a gene called SIRT1 and a plant compound found in red wine called resveratrol can protect against neuron degeneration in a mouse model of Alzheimer's disease and amyotrophic lateral sclerosis. The researchers demonstrated that activating SIRT1 and injecting resveratrol, which have both been previously associated with life-span extension in lower organisms, can also prevent cognitive problems in the mice.

The mice used in the study develop an approximation of human neurodegenerative disease over a period of weeks. As neurons in their brains die and lose connections, their spatial learning is impaired, and the mice develop difficulty associating cause and effect. Treatment with resveratrol reduced the death and degeneration of neurons in these mice and also restored their learning abilities to a level comparable to that of normal mice not suffering neurodegeneration. "Thus, resveratrol is not only neuroprotective, it also improves cognitive function after severe neurodegeneration," says Li-Huei Tsai, the professor of neuroscience at MIT who led the research with David Sinclair, a professor of pathology at Harvard. Tsai says this improvement in function suggests that resveratrol has potential for treating human neurodegenerative diseases.

....The study is the first to suggest that resveratrol could actually improve cognitive function in patients with neurodegenerative diseases. "Generally, SIRT1 has been observed to be neuroprotective," says Leonard Guarente, the professor of biology at MIT who uncovered the connection between life span and the yeast equivalent to SIRT1 about 10 years ago. What's new about Tsai and Sinclair's work, he says, is its demonstration that activating SIRT1 prevents cognitive decline in mice with neurodegenerative disease. The study shows that "resveratrol can protect against memory loss and learning decline," says Guarente, who was not involved with the research.

Guarente says the study suggests that compounds that can activate SIRT1 could be used to treat neurodegenerative disease in humans as long as they can pass through the blood-brain barrier. This membrane surrounding and protecting the brain from chemicals in the blood presents a major challenge to any researcher developing drugs that target the brain. Mice in the study received injections of resveratrol directly into blood vessels in their brains, which would not be practical in human patients.

Source

This type of regenerative gene control via phyto-nutrients is particularly encouraging, given the most famous source of the nutrient is red wine.

Resveratrol and other phyto-nutrients have significant potential to benefit an aging population in the developed world--far beyond whatever in vivo anti-oxidant activity they may possess. The particular mechanisms of their beneficial potential is yet to be worked out.

Edmonton Aging Symposium--Aubrey de Grey Moderates

Here is the first video from the Edmonton Aging Symposium, provided by The Methuselah Foundation.

Mitochondrial Paradigm for ... Aging and Cancer

In looking at aging, it is not enough to look at the nuclear genome. One must also look at the mitochondrial genome, and how the mitochondria interact with the nuclear genome.

Dr. Wallace looks at the ancient history of mitochondria as a free-living organism, and the subsequent symbiosis of mitochondria living inside eucharyotic cells. Then he looks at the mitochondrial genome and how it might affect a person's prospects for a long healthy life. 58 minutes.