A special breed of mice lived up to three times longer than normal after University of Pittsburgh researchers injected them with stem cells from younger, healthy mice, according to a study being published today in the journal Nature Communications.

Working with mice that are bred to die prematurely, Pitt researchers led by Johnny Huard and Laura Niedernhofer dramatically increased the animals’ lifespans by injecting them in the abdomen with young animals’ muscle stem cells. _Post-Gazette

Keep in mind that this research was done in a special breed of mouse that is programmed to have a shorter lifespan. Additional research will be required to determine if normal ageing mice can benefit from similar treatment.

“We wanted to see if we could rescue these rapidly aging animals, so we injected stem/progenitor cells from young, healthy mice into the abdomens of 17-day-old progeria mice,” Dr. Huard said. “Typically the progeria mice die at around 21 to 28 days of age, but the treated animals lived far longer – some even lived beyond 66 days. They also were in better general health.”

As the progeria mice age, they lose muscle mass in their hind limbs, hunch over, tremble, and move slowly and awkwardly. Affected mice that got a shot of stem cells just before showing the first signs of aging were more like normal mice, and they grew almost as large. Closer examination showed new blood vessel growth in the brain and muscle, even though the stem/progenitor cells weren’t detected in those tissues.

In fact, the cells didn’t migrate to any particular tissue after injection into the abdomen.
“This leads us to think that healthy cells secrete factors to create an environment that help correct the dysfunction present in the native stem cell population and aged tissue,” Dr. Niedernhofer said. “In a culture dish experiment, we put young stem cells close to, but not touching, progeria stem cells, and the unhealthy cells functionally improved.” _MedXpress

Stem cells can conceivably be used for many purposes, in the treatment of ageing. In the case of the above research, the stem cells apparently secreted some type of hormonal growth factor which was lacking in the progeria mice.

But in future, more sophisticated uses of stem cells to treat ageing, stem cells will be used for tissue replacement, organ regeneration and replacement, humoral factor replacement, and probably other uses not yet discovered.

Al Fin Longevity

An overwhelming number of natural products and nutraceuticals vie for our attention. Each is associated with a variety of claims of health benefits, often without any reference to the experimental evidence (if any) supporting those claims – or with reference only to dubious, poorly controlled studies in backwater journals. I don’t spend a lot of time following these compounds, but occasionally one gets mentioned often enough that is breaks through into the literature (e.g., resveratrol, green tea, carnitine/lipoate, or other supplements) and I mention it here.

If only because of the size of the heap, I nonetheless still suspect that there’s a pony in there somewhere; I’ve often wished I had the time to do a comprehensive literature review of my own, so that I could identify the compounds whose associated claims are supported by the best evidence. Now it looks like I can start wishing for something else, because someone did it for me.

At the (amazing) blog Information is Beautiful, David McCandless and Andy Perkins have assembled a “generative data-visualisation of all the scientific evidence for popular health supplements“. In David’s words:

I’m a bit of a health nut. Keeping fit. Streamlining my diet. I plan to live to the age of 150 in fact. But I get frustrated by constant, conflicting reports and studies about health supplements.

Is Vitamin C worth taking or not? Does Echinacea kill colds? Am I missing out not drinking litres of Goji juice, wheatgrass extract and flaxseed oil every day?

In an effort to give myself a quick reference guide, I dove into the scientific evidence and created a visualization for my book. And then worked with the awesome Andy Perkins on a further interactive, generative “living image”.

The image itself is dynamic with respect to both user input about what information is desired, and introduction of new data – it is based on the information in a spreadsheet, which can be updated (new compounds, or information about compounds already mentioned), altering the visual rendering the dynamic image. You can play with the image here; I’ve attached a still snapshot below.

The rendering is imperfect (as also discussed elsewhere): More reliable claims are near the top, and more dubious claims are near the bottom, but this positioning is the result of a single variable, “evidence,” which may the based largely on a citation count. This is a problem because not all citations that mention a compound should be weighted equally; furthermore, it’s not clear how conflicting claims end up getting counted. The abstraction of a complex body of data into a single number unquestionably involves some judgment calls that could be made differently – that’s not necessarily a lethal criticism, but the process should be as transparent as possible.

On a visual level, the image is attractive, but color is mostly a wasted variable: position along the color spectrum is synonymous with height — except in the case of orange, which indicates a compound with “low evidence, promising results”. The orange compounds are still assigned an evidentiary weight, according to an algorithm I can’t fathom; this is particularly confusing at both ends: beta-glucan is in the “high evidence” position, which seems to contradict the label’s definition (“low evidence”); whereas noni and astragalus are in the “no evidence” position, raising questions about how there could be “promising results”.

The strength of the project, however, is that it can evolve; the creators are already enthusiastically updating it. So far the changes (as detailed in this log) are content-oriented; one hopes that the methodology of generative data visualization will also enjoy improvements as time goes by.

(For another example of user-driven visualization, see the Timeline of Discoveries in the Science of aging, which we discussed here previously (1 2). That piece hasn’t been updated in a while – perhaps it could use some new contributors.)

Ouroboros

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.

Al Fin Longevity

The ongoing study of current cognitive enhancers such as those in the table above, have given us scattered hints as to what future therapies might offer. Here is a short list of possible future targets for cognitive therapies:

Among targets under investigation, cholinergic receptors have received much attention with several nicotinic agonists (α7 and α4β2) actively in clinical trials for the treatment of AD, CIAS and attention deficit hyperactivity disorder (ADHD). Both glutamatergic and serotonergic (5-HT) agonists and antagonists have profound effects on neurotransmission and improve cognitive function in preclinical experiments with animals; some of these compounds are now in proof-of-concept studies in humans. Several histamine H3 receptor antagonists are in clinical development not only for cognitive enhancement, but also for the treatment of narcolepsy and cognitive deficits due to sleep deprivation because of their expression in brain sleep centers. Compounds that dampen inhibitory tone (e.g., GABAA α5 inverse agonists) or elevate excitatory tone (e.g., glycine transporter inhibitors) offer novel approaches for treating diseases such as schizophrenia, AD and Down syndrome. In addition to cell surface receptors, intracellular drug targets such as the phosphodiesterases (PDEs) are known to impact signaling pathways that affect long-term memory formation and working memory. Overall, there is a genuine need to treat cognitive deficits associated with many neuropsychiatric conditions as well as an increasingly aging population. _Source

It is important for us, at the outset, to take as realistic a viewpoint toward the possibility of meaningful cognitive enhancement as possible. The Likelihood of Cognitive Enhancement (Lynch et al 2011 PDF) is a useful introduction to many of the practical issues that need to be faced from the very beginning of this enterprise. Cognitive Enhacement: Promises and Perils (Hyman 2011 PDF) is a less technical introduction to the topic, perhaps more accessible to most laymen.

Cognitive Enhancement as a Pharmacotherapy Target for Stimulant Addiction (Sofuoglu 2010) looks at the use of cognitive enhancers as possible treatments for cocaine and methamphetamine addictions. Long term and heavy use of these drugs leads to cognitive deficits which make it even more difficult for a person to stop using these drugs and lead a “normal” life. The restoration of cognitive function is likely to provide a certain amount of “mental fortification” to allow at least some addicts to turn away from the dead end lifestyle. Similarly, restoration of cognitive function in persons suffering from age-related neurodegeneration is more likely to allow the person to participate in normal social interaction, and to undertake some level of responsibility, and perhaps productive activity.

Emerging Pharmacotherapies for Neurodevelopmental Disorders (Wetmore et Garner 2010) looks at the use of cognitive enhancers for persons who suffer from neurodevelopmental disorders such as Down’s Syndrome, Fragile X, autism, etc. Given the overlap of mechanisms between some of the cognitive deficits in developmental disorders and ageing-related cognitive deficits, some of the coming developments in this area of pharmacotherapy should also prove quite helpful for treating age-related dementias.

As more is learned about the time-course of dysfunction in NDDs [neurodevelopmental disorders], targeting of therapies to the existing brain state may be improved. Moreover, individuals with NDDs have multiple cognitive and behavioral disabilities, and a particular drug therapy may improve only a subset of cognitive functions. Thus, a combination of complementary drugs may offer the most benefit by addressing deficits in attention, arousal, information processing, or depression.
…
The NDDs discussed here are phenotypically diverse yet linked by common mechanisms of dysfunction, including abnormal gene dosage, imbalance among neurotransmitter systems, and local protein translation (Fig. 2). A particular NDD can be caused by mutations in multiple genes, underscoring the convergence of dysfunction in key biochemical pathways. _Source

Finally, I would like to append to this entry some material from an earlier Al Fin article, which provides a few hints of future drug targets, as well as links to related material:

AMPAkines
CREB
PDE Inhibitors(4,10)
Nicotinic Alpha-7 agonists
mGluR antagonists
5HT6 antagonists

Frontrunners in the pharmaceutical race for smarter, better memory drugs include Memory Pharmaceuticals, Cortex Pharmaceuticals, Saegis Pharmaceuticals, Helicon, Lilly, Pfizer, Wyeth, Merck, Sention and many others. The precedent of approving drugs for erectile dysfunction (ED)–a lifestyle drug–suggests that smart drugs will eventually be approved for drooping memories as well.

Further Reading:

Molecules for Memory

Nootropics

Smart Drugs: What Are the Prospects?

Shaping the Brain with Smart Drugs (Gazzaniga)

CREB and Memory (basic neuroscience)

CREB, Synapses, and Memory Disorders

Hat tip Advanced Nano and Kurzweilai.net

Al Fin Longevity

the naked mole rat has what could be the most extraordinary set of natural defenses ever found in a mammal. A mouse’s life is short and terrible—even in the lab, with plenty of food and a steady thermostat, it lasts for just three or four years at the most. A naked mole rat shows no sign of aging until it’s a quarter of a century old. Blind and plump, it skitters around in a hazmat suit of its own creation. _Slate

Naked mole rats appear impervious to radiation and carcinogens of all kinds. These naked mole rats are incredibly reluctant to get cancer. And that is not the half of it:

In 2004, Buffenstein and her students tried one of these shortcuts. They placed some mole rats in a gamma chamber and blasted their pale, pink bodies with ionizing rays. The animals were unimpressed. When I visited Buffenstein’s lab this past July, many were still alive, skittering through the plastic tubes of their basement habitat at the Barshop Institute for Longevity and Aging Studies.

Four years later, Buffenstein…infected cells from a naked mole rat with a virus designed to corrupt their nuclei with the cancer-causing genes SV40 TAg and Ras. Then she slipped those cells into a live mouse, under the skin behind its ear. If you do the same using infected material from a mouse or a rat, or even a cow or a human, the transplant quickly grows into a deadly tumor, invading nearby fat and muscle tissue. But when Buffenstein and her colleagues used cells from a naked mole-rat, nothing happened.

…Earlier this year, one of Buffenstein’s graduate students tried smearing the skin of half a dozen naked mole rats with a pair of vicious carcinogens: A synthetic compound called DMBA and an inflammatory agent known as TPA. When the same toxic pairing was applied to regular Black-6 lab mice as an experimental control, a cluster of tumors popped up within weeks. Every single mouse had cancer, and every single mouse died. The naked mole rats went on skittering through their tubes.

…Her latest assault involves pouring carcinogens down the mole rats’ throats in a last-ditch effort to induce liver or mammary cancer. But that may not work, either. For years, Buffenstein’s laboratory Rasputins have been irradiated, poisoned, and heated up; their cells dosed with every imaginable pollutant—chemotherapies, oxidative stressors, and heavy metals—with little or no effect. “You name it,” the professor says, “we tried all the kinds of toxins that are out there, and the naked mole rat seems to be very resilient and resistant.”

…The very thing that makes naked mole rats so interesting to Buffenstein—an astonishing vitality that lasts for decades—only makes her research more difficult. “You’re caught between a rock and a hard place, because they live so long that your grandchildren have to finish the studies you start.” Still, slow science may have rich rewards, and the decisions we make today—on whether to invest in new model organisms or build out the ones we already have—are sure to have profound effects on the (human) generations to come. _Slate

The above Slate article by Daniel Engber is an excellent example of good science writing. We learn about the things that make the naked mole rat intriguing as an object of study, then we learn why the biomedical funding establishment is so biased against funding studies using naked mole rats. The life of science is full of such conflicts, which can drive scientists out of the lab entirely if they cannot learn to deal with the frustrating politics and grant grubbing.

No human would want to trade places with a naked mole rat, even if it meant living 10 times longer — and in better health — than the average human. But we might want some of the naked rats resistance to cancer and degenerative change.

Human gerontologists are not trying to discover the path to immortality. They are not even trying to give humans the relative advantage in life span that the naked mole rat has over other rodents. What human scientists are trying to achieve is fairly modest — they want to find a way to delay the signs of aging for roughly seven years beyond the average:

THE TARGET What we have in mind is not the unrealistic pursuit of dramatic increases in life expectancy, let alone the kind of biological immortality best left to science fiction novels.20 Rather, we envision a goal that is realistically achievable: a modest deceleration in the rate of aging sufficient to delay all aging-related diseases and disorders by about seven years.21 This target was chosen because the risk of death and most other negative attributes of aging tends to rise exponentially throughout the adult lifespan with a doubling time of approximately seven years.22 Such a delay would yield health and longevity benefits greater than what would be achieved with the elimination of cancer or heart disease.23 And we believe it can be achieved for generations now alive.

If we succeed in slowing aging by seven years, the age-specific risk of death, frailty, and disability will be reduced by approximately half at every age. People who reach the age of 50 in the future would have the health profile and disease risk of today’s 43-year-old; those aged 60 would resemble current 53-year-olds, and so on. Equally important, once achieved, this seven-year delay would yield equal health and longevity benefits for all subsequent generations, much the same way children born in most nations today benefit from the discovery and development of immunizations.

A growing chorus of scientists agrees that this objective is scientifically and technologically feasible. How quickly we see success depends in part on the priority and support devoted to the effort. Certainly such a great goal – to win back, on average, seven years of healthy life – requires and deserves significant resources in time, talent and treasury. But with the mammoth investment already committed in caring for the sick as they age, and the pursuit of ever-more expensive treatments and surgical procedures for existing fatal and disabling diseases, the pursuit of the Longevity Dividend would be modest by comparison. In fact, because a healthier, longer-lived population will add significant wealth to the economy, an investment in the Longevity Dividend would likely pay for itself. _”TheScientist“_via_NR

Can we learn anything toward that end, from the naked mole rat? Quite possibly. But we have to be willing to put in the time and expense to learn how to transfer the lessons from that exceptional rodent to the human species.

Al Fin Longevity

Animal studies support a cancer-promoting role for fat, and in humans, epidemiological data strongly suggest that dietary fat intake may be associated with incidence and mortality of cancers of the breast, colon, rectum, and prostate. There are also data implicating fat in cancers of the ovaries, uterus, pancreas, and lung, but the evidence is not as strong. There is still a debate as to whether it is total dietary fat, specific fats, or total calories that are involved in carcinogenesis. In any event, cancers of breast, colon, and prostate are highest in North America and western Europe and lowest in Asia, and are directly related to the intake of total fat in the diet even when adjusted for total calories. (more…)

Abuse of drugs and alcohol is not uncommon among the elderly. The high rate of prescribed medication use, increased physiological sensitivity to drug effects, and the danger of interaction effects of multiple medications and/or alcohol place older adults at high risk for deliberate or accidental misuse of drugs or alcohol. In addition, some older adults turn to alcohol to help cope with stressful life events, thus increasing the risk of addiction or toxic interactions. (more…)

Depression is the most common mental health problem in the elderly. While the incidence in community-dwelling older adults is no higher than in the general population, the risk increases significantly with medical illness or institutionalization. Depression is probably the best researched of the psychiatric disorders in the elderly, with epidemiological evidence indicating that older adults have the highest suicide rate of any age group (one-fourth of all suicides are carried out by persons age 60 or older by taking sleeping pills suicide). (more…)

Cognitive-Behavioral Interventions Research documenting the efficacy of Cognitive-Behavioral Interventions in treating the psychological problems of older adults is encouraging. Cognitive-Behavioral Interventions has been shown to reduce symptoms of depression, anxiety, and somatic complaints (e.g., chronic pain elderly, insomnia) in multiple controlled studies. However, research also has indicated that there may be multiple variables to consider in determining whether Cognitive-Behavioral Interventions is the best approach to use with a specific patient and a specific problem. For example, differential effectiveness of Cognitive-Behavioral Interventions compared to other forms of psychotherapy is less certain. (more…)

Beneficiaries of the Medicare program have three rehabilitation-related benefits established by federal statute: physical therapy rehabilitation, occupational therapy, and speech-language therapy (speech-language pathology). All therapists, who must be graduates of accredited programs, must pass a national examination and be licensed, certified, or registered in their respective professions within the state in which the services are furnished. Medicare covers services that are necessary and likely to result in improvement in a reasonable period of time. Medicare does not currently regard prevention services provided by therapists as falling under therapy benefits and will not cover services intended to maintain a current level of function. (more…)