Good News for Mouse Lovers

The following article is cross-posted from Al Fin Longevity


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.

Young Blood in Old Veins: Grasping for Immortality

Tissue from the hippocampus of old mice given young blood showed changes in the expression of 200 to 300 genes, particularly in those involved in synaptic plasticity, which underpins learning and memory. They also found changes in some proteins involved in nerve growth.

The infusion of young blood also boosted the number and strength of neuronal connections in an area of the brain where new cells do not grow. This didn't happen when old mice received old blood. _NewScientist

There is something about young blood that transforms old tissues -- from the genetic level upwards. Those hormonal messengers and other signaling factors that are more prevalent in younger blood make their way into the cell and cell nucleus, transforming gene expression to more closely approximate the gene expression of a younger animal.

But the mystery remains: what exactly is it about young blood that old blood doesn't have? "We have not identified any individual factors responsible for the rejuvenating effects of young plasma yet," says Tony Wyss-Coray, also at Stanford. His team is now trying to identify possible candidates such as lipids and hormones.

Villeda is hopeful the results might one day translate to humans since the components of blood that change with age in mice mirror those in humans. _New Scientist

Abstract of original study from Nature:

In the central nervous system, ageing results in a precipitous decline in adult neural stem/progenitor cells and neurogenesis, with concomitant impairments in cognitive functions1. Interestingly, such impairments can be ameliorated through systemic perturbations such as exercise1. Here, using heterochronic parabiosis we show that blood-borne factors present in the systemic milieu can inhibit or promote adult neurogenesis in an age-dependent fashion in mice. Accordingly, exposing a young mouse to an old systemic environment or to plasma from old mice decreased synaptic plasticity, and impaired contextual fear conditioning and spatial learning and memory. We identify chemokines—including CCL11 (also known as eotaxin)—the plasma levels of which correlate with reduced neurogenesis in heterochronic parabionts and aged mice, and the levels of which are increased in the plasma and cerebrospinal fluid of healthy ageing humans. Lastly, increasing peripheral CCL11 chemokine levels in vivo in young mice decreased adult neurogenesis and impaired learning and memory. Together our data indicate that the decline in neurogenesis and cognitive impairments observed during ageing can be in part attributed to changes in blood-borne factors. _Nature

The study linked above focused on the effect of young blood on brain tissue and neurogenesis. It is likely that humoural factors more prominent in the blood of younger animals are capable of transforming the gene expression of most tissues of older animals -- not just the brain. At the same time, destructive factors -- pro-inflammatory cytokines for example -- that are more prevalent in the blood of older animals, are less likely to be present at high levels in younger animals' blood.

Dr Villeda hopes the results might one day translate to humans.

He told the Guardian newspaper online there was no reason not to think that, at some point in the future, people in their 40s or 50s could take therapies based on the rejuvenating chemical factors in younger people's blood, as a preventative against the degenerative effects of ageing. _Australian

This research should stimulate dozens of new studies, seeking out the good factors in young blood and the bad factors in old blood. Once these entities are identified, the quest to understand each factor -- good and bad -- will trigger dozens of new studies in its own right. In other words, Stanford's research on young blood into old animals is likely to trigger hundreds of new research studies -- a veritable boon for research into dozens of human maladies, including ageing.

More: Another approach to rejuvenating old cells (h/t Brian Wang)

Things are likely to become more interesting, as long as the scientific free for all of conflicting ideas is allowed to proceed unchecked by ideology and politics.

Building Two Pillars of SENS

Aging Damage	Discovery	SENS Solution
Cell loss, tissue atrophy	19551	Stem cells and tissue engineering (RepleniSENS)
Nuclear [epi]mutations (only cancer matters)	19592, 19823	Removal of telomere-lengthening machinery (OncoSENS)
Mutant mitochondria	19724	Allotopic expression of 13 proteins (MitoSENS)
Death-resistant cells	19655	Targeted ablation (ApoptoSENS)
Tissue stiffening	19586, 19817	AGE-breaking molecules (GlycoSENS); tissue engineering
Extracellular aggregates	19078	Immunotherapeutic clearance (AmyloSENS)
Intracellular aggregates	19599	Novel lysosomal hydrolases (LysoSENS)

The "seven pillars of SENS anti-aging strategies" are shown in the table above, with a timeline of the discovery of their importance shown in the image below.

Important progress has recently been made on two of the pillars of SENS: Correcting for mutant mitochondria, and an improved clearing of cellular junk.

First, correcting human mitochondrial mutations:

Researchers at the UCLA stem cell center and the departments of chemistry and biochemistry and pathology and laboratory medicine have identified, for the first time, a generic way to correct mutations in human mitochondrial DNA by targeting corrective RNAs, a finding with implications for treating a host of mitochondrial diseases. Mutations in the human mitochondrial genome are implicated in neuromuscular diseases, metabolic defects and aging. There currently are no methods to successfully repair or compensate for these mutations, said study co-senior author Dr. Michael Teitell, a professor of pathology and laboratory medicine and a researcher with the Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research at UCLA.

Between 1,000 and 4,000 children per year in the United States are born with a mitochondrial disease and up to one in 4,000 children in the U.S. will develop a mitochondrial disease by the age of 10, according to Mito Action, a nonprofit organization supporting research into mitochondrial diseases. In adults, many diseases of aging have been associated with defects of mitochondrial function, including diabetes, Parkinson's disease, heart disease, stroke, Alzheimer's disease and cancer.

"I think this is a finding that could change the field," Teitell said. "We've been looking to do this for a long time and we had a very reasoned approach, but some key steps were missing. Now we have developed this method and the next step is to show that what we can do in human cell lines with mutant mitochondria can translate into animal models and, ultimately, into humans."

The study appears March 12, 2012 in the peer-reviewed journal Proceedings of the National Academy of Sciences. _esciencenews

More at the link.

Next, clearing cellular trash aggregates:

A University of Michigan cell biologist and his colleagues have identified a potential drug that speeds up trash removal from the cell's recycling center, the lysosome.

The finding suggests a new way to treat rare inherited metabolic disorders such as Niemann-Pick disease and mucolipidosis Type IV, as well as more common neurodegenerative diseases like Alzheimer's and Parkinson's, said Haoxing Xu, who led a U-M team that reported its findings March 13 in the online, multidisciplinary journal Nature Communications.

"The implications are far-reaching," said Xu, an assistant professor of molecular, cellular and developmental biology. "We have introduced a novel concept—a potential drug to increase clearance of cellular waste—that could have a big impact on medicine." _UMich News

More at the link.

Both of these developments will require a number of years to perfect and shape into useful therapies. But as noted, improved therapies in either domain would provide hope for slowing the ageing process, and for treating many of the degenerative scourges of human existence.

The SENS Foundation has worked to promote research in the seven areas pictured above. And at least partially due to the efforts of SENS, more researchers and funding agencies are picking up the same themes.

Cross-posted to Al Fin Longevity

Rejuvenating 100 Year Old Cells: Steps to Regenerative Medicine

"Signs of aging were erased and the iPSCs obtained can produce functional cells, of any type, with an increased proliferation capacity and longevity," explains Jean-Marc Lemaitre who directs the Inserm AVENIR team....The age of cells is definitely not a reprogramming barrier. _SD

Cell Rejuvenation via IPSC
Scientists at the Functional Genomics Institute have taken cells donated by persons older than 100 years, and reprogrammed these senescent cells into pluripotent stem cells and embryonic stem cells. These stem cells can then be differentiated into specialised cells for cell, tissue, and organ replacement therapy -- once the details are worked out.

The researchers have successfully rejuvenated cells from elderly donors, some over 100 years old, thus demonstrating the reversibility of the cellular aging process.


To achieve this, they used an adapted strategy that consisted of reprogramming cells using a specific "cocktail" of six genetic factors, while erasing signs of aging. The researchers proved that the iPSC cells thus obtained then had the capacity to reform all types of human cells. They have the physiological characteristics of "young" cells, both from the perspective of their proliferative capacity and their cellular metabolisms.


Researchers first multiplied skin cells (fibroblasts) from a 74 year-old donor to obtain the senescence characterized by the end of cellular proliferation. They then completed the in vitro reprogramming of the cells. In this study, Jean-Marc Lemaitre and his team firstly confirmed that this was not possible using the batch of four genetic factors (OCT4, SOX2, C MYC and KLF4) traditionally used. They then added two additional factors (NANOG and LIN28) that made it possible to overcome this barrier.


Using this new "cocktail" of six factors, the senescent cells, programmed into functional iPSC cells, re-acquired the characteristics of embryonic pluripotent stem cells.
In particular, they recovered their capacity for self-renewal and their former differentiation potential, and do not preserve any traces of previous aging. To check the "rejuvenated" characteristics of these cells, the researchers tested the reverse process. The rejuvenated iPSC cells were again differentiated to adult cells and compared to the original old cells, as well as to those obtained using human embryonic pluripotetent stem cells (hESC).


...The results obtained led the research team to test the cocktail on even older cells taken from donors of 92, 94 and 96, and even up to 101 years old. "Our strategy worked on cells taken from donors in their 100s. The age of cells is definitely not a reprogramming barrier." He concluded. "This research paves the way for the therapeutic use of iPS, insofar as an ideal source of adult cells is provided, which are tolerated by the immune system and can repair organs or tissues in elderly patients." adds the researcher.


...Inserm's AVENIR "Genomic plasticity and aging" team, directed by Jean-Marc Lemaitre, Inserm researcher at the Functional Genomics Institute (Inserm/CNRS/Université de Montpellier 1 and 2) performed the research. The results were published in Genes & Development on November 1, 2011 _SD

The first use of this new regenerative technology is likely to be cell replacement therapy. But as the methods for growing replacement tissues and organs in the lab are perfected, the methods should be suitable for producing cells to use in growing replacement tissues and organs for purposes of disease treatment and for treating senescence.

Cross-posted to Al Fin Longevity

Old Brains Prefer Young Blood

A paper published today in Nature finds that when younger mice are exposed to the blood of older mice, their brain cells behave more like those found in aging brains, and vice versa. The researchers who carried out the work also uncovered chemical signals in aged blood that can dampen the growth of new brain cells, suggesting that the decline in brain function with age could be caused in part by blood-borne factors rather than an intrinsic failure of brain cells. _TechnologyReview

It has been previously found that young blood can reverse certain signs of aging in the circulatory systems of old mice. Now there is evidence that young blood can help rejuvenate old brains.

To arrive at the discovery, the researchers studied pairs of old and young mice that were literally joined at the hip. They used a technique called parabiosis, in which two mice are surgically joined together along the flank, which causes them to develop a shared circulatory system. The technique has been used to study the development of the blood system, and more recently has been used to investigate the effects of age by joining old and young mice.

Lead author Tony Wyss-Coray, a neuroscientist at Stanford University, says that five weeks after creating these May-December pairings, "we found striking effects both on the young and old brains." The young mice had a reduction in the production of new neurons (neurogenesis), an increase in brain inflammation, and less activity in synapses connecting neurons.

The older mice, in contrast, had an increase in new neurons, less inflammation, and greater activity at synapses. "You could almost call this a rejuvenation effect," Wyss-Coray says.

...To see whether the effect could influence behavior, they injected, in separate experiments, young mice with plasma from older mice and vice versa, and found that old plasma impaired the younger animals' ability to perform learning and memory tasks, whereas young plasma improved the abilities of older mice.

Blood cells from one mouse cannot travel into the brain of the other because of the blood-brain barrier, so the team concluded that free-floating molecules in the blood, capable of passing through, must be responsible for the effects. By comparing more than 60 chemokines—chemical messengers secreted by cells that circulate in the blood—the researchers identified several associated with the detrimental effect of old blood. Administering one of these chemicals, called CCL11, to young mice dampened neurogenesis and impaired learning and memory. CCL11 has been studied for its role in allergies and asthma, but it's not clear how it influences neurons. _TechnologyReview

Does this mean that those of us who wish to stay young will have to prey on our young like vampires, sucking their life's blood for our own sustenance? No. For we are learning how to take our old cells and make them young again, in vitro -- in the test tube. The goal is to do the same thing, only better, and in vivo.

Such cellular rejuvenation treatments are likely to prove excellent stopgap methods of anti-aging, with significant -- but limited -- effects. The lifespans we live will be lived as younger, more vital monkey-men. And that is worth a very great deal.

But if we wish to live significantly longer lives, at significantly higher levels of awareness, intellect, and invention, we will need to go deeper than cellular replacement and humoral replacement therapies of this type.

Taken from an article published at Al Fin Longevity

In Chernobyl, 60 Year Old Men Appear "Not a Day Over 30"

18March2011 Brian Wang has more on this story

"Radiation is good for you," one of them tells me. "Every year I get younger," says another. And another: "I work here so when I come home glowing my wife will think I'm a god."

A particularly hearty-looking man who works as a janitor asks me, "How old do you think I am?"

"Sixty," he answers himself....he looks not a day past 30. _Outside

As of January of this year, Chernobyl is now open to tourism. Over most of what is now the Chernobyl wildlife haven, radiation levels have returned near normal. The wild animal population is thriving, and the people there do not seem to be doing so badly themselves. Particularly so long as they have an ample supply of homemade vodka.

Residents of Chernobyl are not the only ones who claim health benefits from low dose exposure to ionizing radiation. Skim through the research regarding "radiation hormesis" referenced here and here, and you may begin to develop a bit of healthy skepticism toward the "zero tolerance policy" of modern environmental protection law toward low level radiation.

More on hormesis:

Hormesis is the term used to describe biological phenomena that are often adverse or detrimental but become beneficial when applied at low levels. The concept of biological hormesis is as important as that of homeostasis for the survival of the organism. The basic biological trait is the organism�s ability to resist and adapt appropriately to both internal and external stresses, and the hallmark of aging is the organism�s inability to withstand stress. The hormetic phenomenon in aging is characterized as beneficial responses to stress through the physiological adaptations, as exemplified in lifespan extension by irradiation and calorie restriction. Thus, hormesis in aging is the biological adaptive function to resist or blunt the age-related deleteriousness. Such a remarkable biological hormetic effect was shown experimentally by exposing mice to a low dose of gamma irradiation, which extended the lifespan of mice rather than shortening by turmorigenesis. The plausible explanation on this interesting radiation hormesis is that the irradiated mice were able to resist better, because the mild radiation itself is the most effective factor in conditioning for the activation of adaptation. In response to stress, an organism is expected to go through three distinct phases: alarm reaction, resistance phase, and exhaustion phase. According this schema, the adaptability can be developed during the resistance period. This notion is in line with the evolutionary view on the survival for the fittest theory, for which the only possible way to attain the survivability is through the organism�s metabolic and defensive adaptation to deleterious stress. _InnoVita

More on hormesis and ageing from an abstract in Ageing Research Reviews:

Hormesis in aging is represented by mild stress-induced stimulation of protective mechanisms in cells and organisms resulting in biologically beneficial effects. Single or multiple exposure to low doses of otherwise harmful agents, such as irradiation, food limitation, heat stress, hypergravity, reactive oxygen species and other free radicals have a variety of anti-aging and longevity-extending hormetic effects. Detailed molecular mechanisms that bring about the hormetic effects are being increasingly understood, and comprise a cascade of stress response and other pathways of maintenance and repair. Although the extent of immediate hormetic effects after exposure to a particular stress may only be moderate, the chain of events following initial hormesis leads to biologically amplified effects that are much larger, synergistic and pleiotropic. A consequence of hormetic amplification is an increase in the homeodynamic space of a living system in terms of increased defence capacity and reduced load of damaged macromolecules. Hormetic strengthening of the homeodynamic space provides wider margins for metabolic fluctuation, stress tolerance, adaptation and survival. Hormesis thus counter-balances the progressive shrinkage of the homeodynamic space, which is the ultimate cause of aging, diseases and death. Healthy aging may be achieved by hormesis through mild and periodic, but not severe or chronic, physical and mental challenges, and by the use of nutritional hormesis incorporating mild stress-inducing molecules called hormetins. The established scientific foundations of hormesis are ready to pave the way for new and effective approaches in aging research and intervention. _ARR

How much is too much, when it comes to radiation? That is difficult to say, at lower doses. Certainly if it is possible to build resistance against radiation and other sources of normal wear and tear, wouldn't most people want to do so?

A dangerous dose is hard to pin down. Worldwide, for most people, those daily microrems add up to about 360 millirems per year. Scientists agree that humans can safely handle 1,000 a year. Astronauts on the International Space Station receive 18,000 millirems of cosmic radiation over six months—but it's once in a lifetime, so it's seen as an acceptable, voluntary risk. But edge that up to 30,000 millirems and you're looking at what caused increased cancer rates among the blast survivors of Hiroshima and Nagasaki. And yet animals can handle even more than this: large mammals and birds are generally safe with 36,000 per year, small ones with even higher doses, and reptiles with higher still. The more complex the animal, the more sensitive it is. _Outside

Of course, animals spend more time outside under the ionizing radiation of the sun, than most modern humans. Perhaps the natural radiation protection exhibited by animals is a manifestation of hormesis?

As long as government-sanctioned science shies away from the topic of "safe levels of low level radiation," we may find it difficult to learn about this topic. With government becoming the largest financier of scientific research, human science is falling into something of a rut. Government bureaucracies are by nature conservative and self-serving. Naturally the science which such bureaucracies are willing to finance and publish, will be the kind of science which justifies the existence and mission of such bureaucracies. They're the government. They're here to help you. Or else.

How will we all survive after the house of cards crashes down? If there is life after a Chernobyl apocalypse, perhaps there could even be life after mega-government breakdown? It may be time for individuals to begin planning for interesting times ahead.

See you in Chernobyl?

Can We Learn to Make the Brain Last 1000 Years?

Aubrey de Grey claims that the first person to live 1,000 years is alive right now. Perhaps. But would anyone alive right now wish to live 1,000 years with a senile brain? Probably not. That is why it is so important to learn all we can about our brains, so that we can make the necessary improvements that will allow us to stay sharp, clear, and responsive to the many changes that the next 1,000 years will bring.

A World of Manics, Where No One is Depressed?

University of Maryland researchers have taken mice and knocked out PKCI/HINT1 genes -- resulting in mice that do not get depressed or anxious.

Wang said, "Although we don't yet know why the deletion of the gene altered the mood status of the mice, what we have learned about the importance of this gene in mood function and its involvement in human mental disorders is interesting. The protein encoded by this gene could be a potential drug target for development of diagnostic or therapeutic agents that one day might be used for depression, bipolar or schizophrenia disorders. In addition, the knockout mice might be useful as a model to study mania, as there is no other animal model available yet. __MNT

When thrown in the deep end of the pool, these PKCI/HINT1 knockout mice never gave up in despair, when all other mice simply rolled over and drowned. They were literally "never say die" mice. Imagine a world of such people.

Excitable Nerves, They All Said

Sometimes nerves can "excite themselves to death." This over-excitation of NMDA glutamate receptors may lead to Alzheimer's, Parkinson's, and multiple sclerosis -- among other neurodegenerative diseases.

....the N-methyl-D-aspartate receptor belongs to a family of cellular receptors that mediate excitatory nerve transmission in the brain.


Excitatory signals represent the majority of nerve signals in most regions of the human brain. One theory of causation in Alzheimer's, Parkinson's and multiple sclerosis posits that excessive amounts of the excitatory neurotransmitter, glutamate, can cause an overstimulation of glutamate receptors, including the NMDA receptor. Such excitotoxicity, the theory holds, can cause nerve-cell death and subsequent neurological dysfunction.


...The search is well under way for molecules that can shut down the NMDA receptor with much greater specificity. _MNT

Memories to Last 1000 Years?

Humans have short term memories (STMs) and long term memories (LTMs). Short term memory is necessary for maintaining a train of thought, or for remembering why you tied that string around your finger an hour or two ago. Long term memory is for remembering things that happened to you more than a day or so ago. These memories are formed and farmed out by the hippocampus, and the system usually works well for a lifespan of 70 or 80 years. But what happens when we live 1,000 years, and desperately need to remember something that happened 899 years ago?

Scientists have known that memories first form in the hippocampus and are later transferred to long-term storage in other parts of the brain. For some amount of time the memory resides both in the hippocampus and elsewhere in the brain. What’s not been known is how, after a few months or years, the memory is gradually cleared from the hippocampus.


Researchers have also debated the role of neurogenesis in learning and memory. The hippocampus is one of only two places in the adult brain where scientists know that new neurons form. On the basis of previous studies, many researchers think new neurons stabilize memory circuits or are somehow otherwise necessary to form new memories.


The new study suggests the opposite: Newborn neurons weaken or disrupt connections that encode old memories in the hippocampus.


Kaoru Inokuchi, a neuroscientist at the University of Toyama in Japan, and his colleagues used radiation and some genetic tricks to block neurogenesis in rats and mice that had been trained to fear getting a mild electric shock when placed in a particular cage. Control animals, with normal neurogenesis, eventually were able to bypass their hippocampi and retrieve the fear memory directly from long-term storage. But animals in which neurogenesis had been blocked still depended on the hippocampus to recall the fear memory, the researchers found.


Running on an exercise wheel, which boosts neurogenesis, also sped the rate at which old memories were cleared from the hippocampus. __Wired

Surviving the Addiction Bottleneck

The human brain has to survive through the treacherous years of childhood, adolescence, and early adulthood in order to gain the wisdom and experience to know how to live, and what to avoid like the plague. Children, adolescents, and young adults are prone to experimenting with drugs, alcohol, and high-risk / low reward behaviours. If the child becomes a crack whore or even an adolescent drunk or pothead like the US president, the 1,000 year prognosis can be very grim.

We need good ways of reversing the brain warp induced by early and habitual drug use.

Medical researchers led by Stephen Dewey at The Feinstein Institute for Medical Research and Dr. Jonathan Brodie of New York University School of Medicine recruited parolees who were cocaine dependent, each using an average of two grams of cocaine daily for nine years.


While half the participants in the study received a placebo powder mixed into their juice each day, half got a powder containing vigabatrin. After three months, 14 of the 50 study participants who got vigabatrin each day were able to abstain from cocaine use during the final three weeks of the study, compared with only 4 of the 53 who received the placebo. _MoneyTimes

It's a start. And in animals, the same drug reduces drug use for most every addictive substance. Of course, it will be harder to make up for the psychological neotenisation caused by poor childraising, abominable educational practises, and a horrifically dumbed down popular culture.

Does Evolution's Arrow Point to Smaller Human Brains?

Human populations that evolved nearer the equator ended up with generally smaller brains, and typically with lower IQ, than human populations that evolved farther from the equator. Anthropologist John Hawks says that the future may be bringing yet smaller brains to the entire global population.

“We know the brain has been evolving in human populations quite recently,” University of Wisconsin-Madison (UWM) paleoanthropologist John Hawks explains, quoted by LiveScience.

“When it comes to recent evolutionary changes, we currently maybe have the least specific details with regard [to] the brain, but we do know from archaeological data that pretty much everywhere we can measure – Europe, China, South Africa, Australia – that brains have shrunk about 150 cubic centimeters, off a mean of about 1,350. That's roughly 10 percent. As to why is it shrinking, perhaps in big societies, as opposed to hunter-gatherer lifestyles, we can rely on other people for more things, can specialize our behavior to a greater extent, and maybe not need our brains as much,” the expert adds. _Softpedia

Modern cultures of hyper-specialisation may lead to even greater shrinking of the human brain. That could be bad for that 1,000 year lifespan.

Smaller brains are typically less intelligent, and will probably be less able to adapt to the lightspeed changes that will hit human populations like truckloads of bricks, every few years to every few dozen years.

Cross-posted in Al Fin Longevity

....And That is the Reason That My Skin is Blue

It isn't easy to live longer than a century. A human being requires some help to avoid cancer, heart disease, Alzheimer's, and other maladies that cut a life short of its useful span. Methylene Blue, a simple heterocyclic aromatic, can be of some benefit in that regard.

A new study conducted by researchers at Children's Hospital & Research Center Oakland shows that a century-old drug, methylene blue, may be able to slow or even cure Alzheimer's and Parkinson's disease. Used at a very low concentration – about the equivalent of a few raindrops in four Olympic-sized swimming pools of water – the drug slows cellular aging and enhances mitochondrial function, potentially allowing those with the diseases to live longer, healthier lives.

A paper on the methylene blue study, conducted by Hani Atamna, PhD, and a his team at Children's, was published in the March 2008 issue of the Federation of American Societies for Experimental Biology (FASEB) Journal. Dr. Atamna's research found that methylene blue can prevent or slow the decline of mitochondrial function, specifically an important enzyme called complex IV. Because mitochondria are the principal suppliers of energy to all animal and human cells, their healthy function is critical. _SD

First the urine turns blue, then the lymph, and finally the skin. It is a bitter pill to swallow, but growing old must be more bitter still.

Finally Getting Respect: Understanding Aging Conference Wrapping Up in Los Angeles

After working in obscurity and semi-respectability for almost a decade, Aubrey de Grey is finally getting the recognition he deserves. The Understanding Aging conference at UCLA is wrapping up after a full weekend of presentations.

Probably the most famous presentation of the weekend to hit the news so far, is the potential "cancer cure" being studied by Wake Forest researcher Zheng Cui, who gave a presentation yesterday at the meetings. Zheng's study involves screening 500 healthy young (under 50) adult volunteers for cancer resistance, then selecting the 100 volunteers with the strongest measured cancer resistance and taking white blood cell (WBC) donations from the 100. These WBC's would then be transfused into cancer patients to determine safety and efficacy of the treatment. The approach has proved very successful in mice. More information here and here.

Another interesting presentation was given by Trevor Marshall reporting on studies linking stem cells, cancer, and bacterial infection.

This comprehensive overview from Brian Wang allows a busy non-attendee to briefly sample the research fare of the busy weekend conference. By doing an internet search using a science search engine, you can often find full text articles by participating authors, which should give considerable background on their current research.

Aubrey de Grey's excellent introduction to SENS anti-aging research, Ending Aging, was published in 2007, but the information in parts of the book is already becoming obsolete by the rapid progress in research labs. Thanks to the energy, ideas, and fund-raising by de Grey and his colleagues, anti-aging research is finally coming out of the closet into the daylight.

Previously published at Al Fin Longevity

Drug to Treat Accelerated Aging in Phase I Trial

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.

Previously published in Al Fin Longevity

MPrize and SENS--Extending the Lifespan

The Methuselah Mouse Prize (Mprize) is a set of contests to develop the longest living mus musculus research mouse. The Mprize is an example of an "Inducement Prize", a cash award created to induce contestants to achieve a notable goal. Other examples of inducement prizes include the recent XPrize won by Burt Rutan's group and the Kremer Prizes for human powered flight won by Paul MacReady's group.

Aubrey de Grey and his SENS group are involved in several approaches to extending human life span, in addition to participating in the Mprize effort.

Peter Thiel, cofounder of Paypal, has recently donated US $3.5 million to SENS research projects. $500,000 was donated for immediate use, and $3 million was contributed in the form of matching grants.

Difficult challenges such as the human longevity challenge, require special champions able to direct scientific researchers toward likely avenues of research and to capture the imagination of donors and the general public. Aubrey de Grey has proven himself up to the challenge on both counts.

For those interested in attending a talk by de Grey, here is his schedule of coming talks. The Edmonton Aging Symposium would be a good choice for Canadians and other North Americans new to the field of life extension.

Humans need longer lives so as to acquire wisdom for future challenges. Although popular "culture" emphasizes amusements and entertainments, there really are serious challenges being met today--although you would never know it from the main stream media. That is one reason why the msm is "old media", obsolete, and a definite "sell."

Sex on the Brain: Apomorphine as Life Extension Aphrodisiac

Apomorphine is an old drug, dating at least back to the 1860s. It has found many uses, including as a treatment for Parkinson's Disease, and a treatment for Erectile Dysfunction. Apomorphine is also an efficient emetic at proper doses. In the context of life extension and longevity, apomorphine has proven to be a good trigger for HGH release. The drug may find uses in cases of stroke and myocardial infarction. Apomorphine is not an opiate analgesic like morphine, and is not addictive.

I suspect that apomorphine will find many more uses, given its multiple potencies. A good sex life is important for a satisfying life, whatever its length, and apomorphine not only induces penile erection, it also is a dopamine agonist, which suggests that the sex drive itself would be stimulated by apomorphine, and the sex act made more pleasurable.

Given the emetic properties of higher doses of apomorphine, it is not likely to become a drug of abuse. And given the several decades since its initial use in humans, the more lethal and disabling side effects of a drug would have been found. In other words, we have a drug, apomorphine, that likely has a positive effect on longevity via HGH release, and a positive effect on sexual desire, performance, and pleasure. Yet very few people have heard of apomorphine.

Here is some recent research on apomorphine from Shanghai:

Apomorphine (APO), a potent D1/D2 dopamine receptor agonist, is currently used as an antiparkinsonian drug. We have shown previously that APO stimulates synthesis and release of multiple trophic factors, such as brain-derived neurotrophic factor (BDNF) and glial cell line-derived neurotrophic factor (GDNF), in both mesencephalic and striatal neurons, thereby effectively preventing dopaminergic neuron loss in vitro. The present study was designed to investigate the effects of APO on fibroblast growth factor-2 (FGF-2) expression and regulation in astrocytes, and furthermore, to identify signaling mechanisms underlying these effects. Here, we show that FGF-2 expression is robustly induced in cultured astrocytes in response to APO. FGF-2 expression was proportional to APO concentration and time-dependent. More at source.

One more thing: apomorphine has been found to be protective of mitochondria in central nervous system neurons and heart muscle. Consider the implications of that when you are putting together your life extension kit.

Glycation in Diabetes and Aging: Routes to Life Extension and Longevity

High blood sugar levels, as are seen in diabetes, insulin resistance, and other forms of hyperglycemia, leads to a process called glycation. Glycation changes the shape and properties of proteins. Crosslinking reduces the flexibility, elasticity, and functionality of the proteins. Furthermore, the chemical modifications of glycation and crosslinking can initiate harmful inflammatory and autoimmune responses. "AGE and nonenzymatic crosslinks are demonstrated to signal inflammatory cytokines, extracellular matrix expansion, angiogenesis, and growth factors." [deGroof] Glycation has been found in connective tissue collagen, arterial collagen, kidney glomerular basement membrane, eye lens crystallins, nerve myelin proteins and in the circulating low-density lipoprotein (LDL) of the blood.

Prolonged glycation leads to creation of advanced glycation end products, AGE. The end result of AGE is all the deadly complications that lead to excessive morbidity and mortality in diabetic patients. Blindness, renal failure, arteriosclerotic heart disease, neuropathies, loss of limbs, etc.

What is not generally known, is that the same process of glycation and AGE formation occurs in normal people, at a much slower rate. You may think that that giant soda, or huge piece of pie is not doing anything bad to your body, but you would probably be wrong. Your connective tissues are being cross-linked beneath your level of awareness. You are ageing prematurely.

This article in Scientific American discussed this issue a few years ago. This brief background article gives more information, with links to more sources.

Various drugs and nutriceuticals have been used to treat glycation and AGE. This article discusses the use of ginger in preventing diabetic kidney damage.
An estimated 19 million people are affected by diabetes in the EU, equal to four per cent of the total population. This figure is projected to increase to 26 million by 2030.

The rhizome of the ginger plant (Zingiber officinale) is a rich source of antioxidants, including gingerols, shogaols, zingerones and other ketone derivatives. It has long been used as a remedy for nausea, especially associated with morning sickness.

The new study, published on-line in Food Chemistry (doi: 10.1016/j.foodchem.2006.01.013), assessed the effects of ginger on the blood antioxidant levels and kidney health of diabetic rat models.

Twenty-four male rats were divided into three groups of eight. The first group (control 1) were healthy rats, the second group (control 2) were diabetic and non-supplemented, and the third group (test) was diabetic and had the diet supplemented with ginger powder as five per cent of the daily food intake.

After eight weeks of supplementation the researchers, led by Dr Ali Taghizadeh Afshari from the Emam Khomeini Hospital, reported: “Antioxidant capacity in the ginger supplemented rats was higher when compared to the other groups.”

The primary drug used to treat glycation and AGE is aminoguanidine. Over the counter nutraceuticals used to treat AGE include carnosine, pyridoxamine, and various forms of thiamine. Ginger may also provide some benefit in preventing diabetic complications, but that research is ongoing.

Glycation end products also accumulate in the brain in Alzheimer's Disease. Scientists are still trying to define any relationship between AGE accumulation in the CNS and neuronal apoptosis. The recent discovery that lower brain insulin may predispose to Alzheimer's Disease probably has something to do with accumulation of AGE.

I will be writing much more on this topic in the future, since it is of great importance in the overall strategy of retarding the ageing process.

Eating Germs to Stay Well

Consider this: you come down with productive cough, fever, chills. The chest Xray indicates an infiltrate in your lung fields. Your doctor prescribes antibiotics, and the symptoms subside, you feel better. What do you do next? According to this newsrelease, you should probably eat some germs. Lactobacilli to be specific. Normal gut flora that make vitamins for you and keep the bad bacteria and yeast from setting up shop in your belly. Read on:

Once outside the womb, we are bombarded by microbes and soon we have 10 times more microbes in our body than the number of cells that make up the human body.

It is the bad microbes that cause disease. Good microbes work with the body's immune system to keep the bad microbes at bay by crowding them out. In the symbiotic relationship between good and bad microbes, recent research has uncovered the importance of these good microbes.

“The good microbes - and this is where probiotics come in - keep the bad microbes in small numbers. But they also stimulate the immune system and improve our digestive function. That's the subject of research that has been going on for years,” Huffnagle says.

Probiotics are bacteria that we eat and they're good for our health. They are found in a number of foods that are readily available in the supermarket, and they taste good. You can support probiotic growth by increasing the amount of cultured dairy products you eat, such as cheeses and yogurt, and the foods that encourage probiotics from these dairy products to multiply even further: spices, tea, red wine, berries, apples and beans.

Huffnagle says that most of these good microbes exist within our body in the digestive track, with the largest number occurring in the small and large intestines.

“It's the job of these good microbes to stimulate our immune system, and the other job they do is to stimulate good digestive health,” he says.

Not only that, but the good bacteria are capable of producing antibiotics that attack bad bacteria. Follow along from this newsreport:

Nisin, a peptide, contains 34 amino acid residues and the unusual amino acids lanthionine, methyllanthionine, dehydroalanine and dehydro-amino-butyric acid. The latter are made by post-translational modification of proteins.

Nisin works well against Gram-positive bacteria and food-borne pathogens that cause botulism and listeriosis because it punches holes into cell membranes and binds to essential molecules in the disease-causing bacteria. Hitting on at least two targets reduces the risk of resistance occurring, van der Donk said.

The researchers synthesized nisin simply in a test tube by using a single cyclase enzyme to re-create the process that normally occurs in a strain of the bacterium Lactococcus lactis found naturally in milk. They demonstrated how just one protein (NisC) makes 10 new chemical bonds in a stereochemically defined fashion. Specifically, they showed that NisC is responsible for the formation of five characteristic thioether rings required for nisin's biological activity.

"Despite all the progress in synthetic chemistry, we cannot come close to making a compound like nisin efficiently," van der Donk said. "Synthetic chemists in the past needed 67 steps to make it, while nature uses just two enzymes. One of these is the cyclase whose activity we have demonstrated in this paper."

Read more here.

When you are born, your gastrointestinal tract is sterile. As soon as you began eating, your gut was colonised by bacteria. If you were breast-fed, you were lucky enough to receive booster nutrients that promoted bifidobacteria, which prevent colonisation by pathogenic bacteria. Other food sources, although nutritious enough, lack that advantage.

Gut bacteria produce vitamins B12 and K for us, as well as keeping out the bad germs. Genetically engineered gut bacteria could do much more for us, and would be a natural way of introducing genetically engineered resveratrol, curcumin, or capsaicin or other natural substances known to counter cancer or promote longevity.

Most of us do not like to think about what goes on inside of us, until we get sick, then we definitely want a physician to think very hard about what is inside of us and how to make it better. But would it not be better to stay well, if you had the choice?

Resveratrol, Quercitin, Calorie Restriction, Longevity

Scientific American's new issue contains an article about "longevity genes" and the search to unlock them. Many articles have been written about the Sir and Sirt genes known to influence longevity in yeast and lower animals. The recent SciAm article brings us fairly up to date on the research of the authors and their associates (David Sinclair and Lenny Guarente).

Calorie restriction (CR) was cited as one of the few maneuvers known to increase lifespan of laboratory animals. Not surprisingly, CR works through the Sirt genes. What was surprising was that resveratrol, found in red grapes and wine, also affects the Sirt genes in much the same way as CR.

First of all, the researchers had to dispense with an old theory that turned out to be false:
The phenomenon (life extension through CR) was long attributed to a simple slowing down of metabolism--cells' production of energy from fuel molecules--and therefore reduction of its toxic by-products in response to less food.

But this view now appears to be incorrect. Calorie restriction does not slow metabolism in mammals, and in yeast and worms, metabolism is both sped up and altered by the diet. We believe, therefore, that calorie restriction is a biological stressor like natural food scarcity that induces a defensive response to boost the organism's chances of survival. In mammals, its effects include changes in cellular defenses, repair, energy production and activation of programmed cell death known as apoptosis.

....Yet if humans are ever to reap the health benefits of calorie restriction, radical dieting is not a reasonable option. Drugs that can modulate the activity of Sir2 and its siblings (collectively referred to as Sirtuins) in a similar manner will be needed. Just such a Sirtuin-activating compound, or STAC, called resveratrol has proven particularly interesting. Resveratrol is a small molecule present in red wine and manufactured by a variety of plants when they are stressed. At least 18 other compounds produced by plants in response to stress have also been found to modulate Sirtuins, suggest?-ing that the plants may use such mole?-cules to control their own Sir2 enzymes.

....Feeding resveratrol to yeast, worms or flies or placing them on a calorie-restricted diet extends their life spans about 30 percent, but only if they possess the SIR2 gene. Moreover, a fly that overproduces Sir2 has an increased life span that cannot be further extended by resveratrol or calorie restriction. The simplest interpretation is that calorie restriction and resveratrol each prolong the lives of fruit flies by activating Sir2.

Resveratrol-fed flies not only live longer, despite eating as much as they want, but they do not suffer from the reduced fertility often caused by calorie restriction. This is welcome news for those of us hoping to treat human diseases with molecules that target Sir2 enzymes. But first we want a better understanding of the role of Sir2 in mammals.

....Increased Sirt1 (the mammalian version of Sir2) in mice and rats, for example, allows some of the animals' cells to survive in the face of stress that would normally trigger their programmed suicide. Sirt1 does this by regulating the activity of several other key cellular proteins, such as p53, FoxO and Ku70, that are involved either in setting a threshold for apoptosis or in prompting cell repair. Sirt1 thus enhances cellular repair mechanisms while buying time for them to work.

....Both our labs are running carefully controlled mouse experiments that should soon tell us whether the SIRT1 gene controls health and life span in a mammal. We will not know definitively how Sirtuin genes affect human longevity for decades. Those who are hoping to pop a pill and live to 130 may have therefore been born a bit too early. Nevertheless, those of us already alive could live to see medications that modulate the activity of Sirtuin enzymes employed to treat specific conditions such as Alzheimer's, cancer, diabetes and heart disease. In fact, several such drugs have begun clinical trials for treatment of diabetes, herpes and neurodegenerative diseases.

The authors were careful not to hype resveratrol, since the research is still ongoing. Other people working with CR are a bit more enthusiastic about resveratrol. Both resveratrol and quercetin have been known for a number of years now to influence Sirt genes. Vitamin and supplement makers are growing quite sophisticated in keeping up with research, and waste no time making natural phytochemicals available to the public, where legal.

It is unlikely that these phytochemicals represent a hazard to the public. Certainly I have been imbibing resveratrol in liquid form for several years now, with no untoward effects noted. Nevertheless, it is hazardous to the purse to buy every supplement that some vitamin salesman promotes. Follow the research and make up your own mind.

I recommend reading the Scientific American article in its entirety.