The INDY gene in fruit flies was one of the earlier discoveries in the genetics of longevity. The initials of the name stand for I'm Not Dead Yet, an allusion to a Monty Python scene and one of many unusual names given to fly genes. You'll find a range of posts on INDY back in the Fight Aging! archives, following the research highlights over the years.

Here is an open access review paper that provides an introduction the INDY and the present state of knowledge regarding its operation when mutated to extend fly life span:

Single gene mutations that extend life span are important tools for discovering pathways underlying aging. Of particular interest have been mutations in genes that are conserved across diverse species, since they suggest common mechanisms for aging regulation. For instance, mutations in insulin signaling genes affect the life span of yeast, worms, fruit flies, and mice ... Mutations in the Indy (I'm Not Dead Yet) gene dramatically extend the life span of the fruit fly, Drosophila melanogaster. Indy encodes the fly homolog of a mammalian di and tricarboxylate transporter involved in regulating plasma and liver levels of citrate and other Krebs cycle intermediates.

...

Reduced expression of fly Indy or two of the C. elegans Indy homologs leads to an increase in life span. Fly and worm tissues that play key roles in intermediary metabolism are also the places where Indy genes are expressed. One of the mouse homologs of Indy (mIndy) is mainly expressed in the liver. It has been hypothesized that decreased INDY activity creates a state similar to caloric restriction (CR). This hypothesis is supported by the physiological similarities between Indy mutant flies on high calorie food and control flies on CR.

...

Flies, worms, and mice show similar physiological changes when INDY expression is reduced, suggesting an evolutionarily conserved role for INDY in the regulation of metabolism. ... The studies on mice further suggest protection from metabolic syndrome and insulin resistance, whether the causative factors are diet or age. INDY is thus an attractive drug target for the amelioration of metabolic disorders associated with diet or advanced age, separate from any effects on longevity.

This is one amongst many longevity-related genes, with likely many more yet to come. There is no shortage of opportunity for research groups wanting to work on the slow and incremental side of the road to the future of human longevity - to produce old-style drugs that change the long term operation of metabolism. The opportunities are there, but this is far from the best path to extending healthy human life spans.

As regular readers know, there is another path forward - the SENS vision of biotechnologies based on repair of damage rather than slowing down the rate of damage. This is likely to be no more costly [and] yet will produce at the end of the day a true cure for aging, not just a marginal benefit and a couple of extra years of life.

Source:
http://www.longevitymeme.org/newsletter/latest_rss_feed.cfm

Parkinson's researchers were among the first to earnestly attempt to create a specific cell type for transplant, and have continued to work at this. The obvious symptoms of Parkinson's are caused by the progressive loss of a thin population of dopamine-producing neurons, and therefore a way of replacing those specialist cells wholesale would be a way to temporarily reverse the course of the disease - perhaps for years or even decades in the best case. Thus these researchers now make up one of the more experienced scientific communities involved in cell therapy research, and can be counted on to rapidly pick up promising new developments in the control and reprogramming of cells. In past years, the focus has been on producing cells for transplant:

• Dopamine Neurons From iPS Cells
• Creating Dopamine Neurons via Transdifferentiation
• Stem Cells Reverse Parkinson's in Rats

Once researchers have demonstrated control over cellular reprogramming, the ability to turn one cell type into another by providing suitable signals, the focus starts to shift away from transplants and on to reprogramming cells in situ: instructing the body - or the brain in this case - to directly produce more of the needed cell type. Here's an example for Parkinson's disease (PD):

In the first step towards a direct cell replacement therapy for Parkinson's, the team reprogrammed astrocytes to dopaminergic neurons using three transcription factors - ASCL1, LMX1B, and NURR1 - delivered with a lentiviral vector. The process is efficient, with about 18 percent of cells expressing markers of dopaminergic neurons after two weeks. The next closest conversion efficiency is approximately 9 percent, which was reported in another study. The dopamine-producing neurons derived from astrocytes showed gene expression patterns and electrophysiolgical properties of midbrain dopaminergic neurons, and released dopamine when their cell membranes were depolarized.

The Penn team is now working to see if the same reprogramming process that converts astrocytes to dopamine-producing neurons in a dish can also work within a living brain - experiments will soon be underway using gene therapy vectors to deliver the reprogramming factors directly to astrocytes in a monkey model of PD.

I'll go out on a limb and suggest that transplants are probably not the be-all and end end-all future of tissue engineering. By the time the 2020s roll around, I'd guess that most of the new therapies moving into US trials and clinical use overseas will be based on delivering increasingly precise and targeted reprogramming instructions into the body rather than introducing new cells or taking the patient's cells and working with them outside the body to produce tissue for transplantation.

Source:
http://www.longevitymeme.org/newsletter/latest_rss_feed.cfm

The onset of Alzheimer's is not a sudden thing, which reinforces the view of it as a lifestyle disease: "The first changes in the brain of a person with Alzheimer's disease can be observed as much as ten years in advance - ten years before the person in question has become so ill that he or she can be diagnosed with the disease. [Researchers] are studying biomarkers - substances present in spinal fluid and linked to Alzheimer's disease. The group has studied close to 140 people with mild memory impairment, showing that a certain combination of markers (low levels of the substance beta-amyloid and high levels of the substance tau) indicate a high risk of developing Alzheimer's disease in the future. As many as 91 per cent of the patients with mild memory impairment who had these risk markers went on to develop Alzheimer's within a ten-year period. In contrast, those who had memory impairment but normal values for the markers did not run a higher risk of getting Alzheimer's than healthy individuals. ... This is a very important finding with regard to the development of new therapies against the disease. All prospective therapies have so far shown to be ineffective in stopping the disease, and many people are concerned that the pharmaceutical companies will give up their efforts in this field. But these failures may depend on the fact that the new therapies were initiated too late. When a patient receives a diagnosis today, the damage has already gone too far." I'm not sold on this last comment, given the evidence suggesting that Alzheimer's symptoms are reversible.

Link: http://www.lunduniversity.lu.se/o.o.i.s?id=24890&news_item=5773

Source:
http://www.longevitymeme.org/newsletter/latest_rss_feed.cfm

The principle use of stem cells in the near future is actually research, not therapy - generating diseased cells to order will lower the cost of better understanding the mechanisms of disease and age-related conditions. For example: "scientists have, for the first time, created stem cell-derived, in vitro models of sporadic and hereditary Alzheimer's disease (AD), using induced pluripotent stem cells from patients with the much-dreaded neurodegenerative disorder. ... It's a first step. These aren't perfect models. They're proof of concept. But now we know how to make them. It requires extraordinary care and diligence, really rigorous quality controls to induce consistent behavior, but we can do it. ... We're dealing with the human brain. You can't just do a biopsy on living patients. Instead, researchers have had to work around, mimicking some aspects of the disease in non-neuronal human cells or using limited animal models. Neither approach is really satisfactory. ... With the in vitro Alzheimer's neurons, scientists can more deeply investigate how AD begins and chart the biochemical processes that eventually destroy brain cells associated with elemental cognitive functions like memory. Currently, AD research depends heavily upon studies of post-mortem tissues, long after the damage has been done. ... The differences between a healthy neuron and an Alzheimer's neuron are subtle. It basically comes down to low-level mischief accumulating over a very long time, with catastrophic results. ... The researchers have already produced some surprising findings. ... In this work, we show that one of the early changes in Alzheimer's neurons thought to be an initiating event in the course of the disease turns out not to be that significant."

Link: http://www.sciencedaily.com/releases/2012/01/120125131029.htm

Source:
http://www.longevitymeme.org/newsletter/latest_rss_feed.cfm

A piece by Aubrey de Grey at the Huffington Post: "as things stand, no amount of insight into age-related pathology can be sufficient to develop outright cures. Some diseases are the end results of aging, just as starvation is the end result of fasting. The nature of aging is such that many age-related infirmities are certain to afflict anyone who lives long enough. And this will remain the case, until a technology is developed which ameliorates the general decrepitude of old age which underlies these diseases. One can, therefore, identify the future direction of medicine by considering the nature of old age itself. What exactly is being taken from us, year after year, from cradle to grave? As time goes by, your hair goes grey, your face gets coarser, you put on weight, you become weaker, more susceptible to disease, and so on. But what do these things have to do with each other? Fortunately, the answer is not so complex as one might anticipate. Most people think of the science of aging as being very incomplete. It is true that aging as a process is not completely understood (biogerontology, the study of aging, involves many competing theories). But the state of disrepair that aging leaves people in can be observed directly, and in great detail. A comparison between two perfect snapshots of old and young tissue would provide us with a very multi-faceted damage report. The aged tissue is riddled with "junk" molecules (by-products of normal metabolic functions) in and between cells, which do not dissipate, not even as the body heals and replenishes itself day in and day out. It would also show an accumulation of unwanted cells, and a depletion of necessary cells. All this damage reduces our tissue function, then our organ function, and eventually it kills us. How this damage accumulates, and how it leads to our demise, are matters of some dispute. But the bare facts of how our tissues alter over time already provide us with enough of a compass with which to chart the future course of medicine."

Link: http://www.huffingtonpost.com/aubrey-de-grey-phd/age-related-diseases_b_985019.html

Source:
http://www.longevitymeme.org/newsletter/latest_rss_feed.cfm

We might look on aging as damage that happens as a stochastic, inevitable consequence of the operation of a biochemical system. So the buildup of chemical gunk between your cells is a part of aging, while those times you managed to break bones in your enthusiasm for life are not aging, despite the fact that what's left in the wake of those unfortunate accidents is definitely damage.

There are always special cases and grey areas worth thinking about, however. Such as teeth, for example, as I was reminded earlier today. Teeth have a pretty hard time of it, actually, when you stop to think about it. Even in this modern age our teeth maintenance technologies remain woefully inadequate in the face of bacterial species that break down enamel, and so our teeth are one of the most failure-prone and damage-prone parts of the body - and they get to the point of painful dysfunction far earlier than the rest of our organs if left to their own devices.

But that isn't aging - it's parasitism, no more aging than the consequences of contracting malaria. It's still something we need to fix, of course, and I post on this and related topics because it is of general interest to anyone who follows research into rejuvenation and regeneration. If most or all of us suffer a particular form of bacterial malfeasance that manages to be as damaging as that which chews upon our teeth, than dealing with that problem has to be included in any general toolkit for enhanced human longevity.

As an aside, I should note that the hard components of teeth do age:

enamel thickness related to age showed a steady decrease, beginning at approximately age 50.

There are apparently chemical composition changes, increased brittleness, and so forth - none of which seems to have much to do with the bacteria that cause cavities.

Another completely unrelated grey area is something I touch on frequently: the structural changes that take place in the <a href=adaptive immune system due to exposure to infectious agents. The adaptive component of the immune system performs throughout life just as it evolved to do - which means it devotes space and cells to remembering the pathogens it has encountered so that it can effectively destroy them in the future. But by continuing to function in this way, it becomes less and less effective over time: in later life too much of its capacity is taken up with memory cells and too little with killer cells. So quite aside from what we might think of as biological aging, the adaptive immune system succeeds itself into an increasingly broken state just by doing its job. Whether or not we call this process aging, it still has to be fixed, auch as by using targeted cell destruction therapies to eliminate memory cells and free up space.

There are other examples. But you get the point: not all of the degenerations that we suffer with advancing age are in fact aging per se, or at least they will not fit into the usefully narrow definitions of aging that I find helpful. They will still need to be addressed, prevented, and their consequences repaired.

Source:
http://www.longevitymeme.org/newsletter/latest_rss_feed.cfm

Via EurekAlert!: "One of the earliest known impairments caused by Alzheimer's disease - loss of sense of smell - can be restored by removing a plaque-forming protein in a mouse model of the disease. The study confirms that the protein, called amyloid beta, causes the loss. ... The evidence indicates we can use the sense of smell to determine if someone may get Alzheimer's disease, and use changes in sense of smell to begin treatments, instead of waiting until someone has issues learning and remembering. We can also use smell to see if therapies are working. ... just a tiny amount of amyloid beta - too little to be seen on today's brain scans - causes smell loss in mouse models. Amyloid beta plaque accumulated first in parts of the brain associated with smell, well before accumulating in areas associated with cognition and coordination. Early on, the olfactory bulb, where odor information from the nose is processed, became hyperactive. Over time, however, the level of amyloid beta increased in the olfactory bulb and the bulb became hypoactive. Despite spending more time sniffing, the mice failed to remember smells and became incapable of telling the difference between odors. The same pattern is seen in people with the disease. They become unresponsive to smells as they age. ... The team then sought to reverse the effects. Mice were given a synthetic liver x-receptor agonist, a drug that clears amyloid beta from the brain. After two weeks on the drug, the mice could process smells normally. After withdrawal of the drug for one week, impairments returned."

Link: http://www.eurekalert.org/pub_releases/2011-11/cwru-eso113011.php

Source:
http://www.longevitymeme.org/newsletter/latest_rss_feed.cfm

Cryonics provider Alcor dedicates a section of their website to challenges and problems, and it is well worth reading: "When you buy a house, the seller is legally obliged to disclose any known defects. When you review a company's annual report, it tells you every problem that could affect the corporate share value. Since arrangements for cryopreservation may have a much greater impact on your life than home ownership or stock investments, we feel an ethical obligation to disclose problems that affect cryonics in general and Alcor specifically. We also believe that an organization which admits its problems is more likely to address them than an organization which pretends it has none. Thus full disclosure should encourage, rather than discourage, consumer confidence. ... As of 2011, Alcor is nearly 40 years old. Our Patient Care Trust Fund is endowed with more than 7 million dollars and is responsible for the long-term care of over 100 cryopatients. In almost every year since its inception Alcor has enjoyed positive membership growth. We are the largest cryonics organization in the world - yet in many respects we are still a startup company. We have fewer than a dozen employees in Scottsdale, Arizona and approximately 20 part-time independent contractors in various locations around the USA, mostly dedicated to emergency standby and rescue efforts. We serve fewer than 1,000 members and the protocols that aid our pursuit of the goal of reversible suspended animation continue to be developed. At the present time the technology required for the realization of our goal far exceeds current technical capabilities. Cryonics will not be comparable with mainstream medicine until our patients can be revived using contemporary technology, and we expect to wait for decades to see this vision fulfilled. Nevertheless, we have made important progress by introducing brain vitrification to improve patient tissue structure preservation. Alcor shares some of the characteristics of startup companies. The organization is understaffed in some important areas and lacks as much capitalization as would be desired to support maximum growth. Limited resources prevent the organization from hiring as many highly qualified and experienced personnel as desired, and sometimes we have to postpone enhancements to equipment and procedures." I think that this is a great document, and Alcor staff are to be congratulated for publishing it - absolutely the right thing to do.

Link: http://alcor.org/problems.html

Source:
http://www.longevitymeme.org/newsletter/latest_rss_feed.cfm

I am not unsympathetic to this viewpoint: recent research shows that "women should raise their glasses to a healthier old age, but we've heard it all before - and just the opposite. ... This is the conclusion of a study of 14,000 female nurses that started in 1976. The brainchild of the Harvard School of Public Health, Boston is the latest result from numerous studies of this nature that have produced all manner of contradictory results. ... In 1976, the [Framington study] is supposed to have shown a connection between menopause and the increased risk of heart disease, which is a bit like saying it found a connection between age and life expectancy - exactly what is one supposed to do with a datum like that? ... At the end of the day, one must ask what is the point of such studies, and specifically what is the point of a study that attempts to link the consumption of wine by women with longevity, especially when Marie Lloyd was telling us a little of what you fancy does you good way back in 1915? Rather than mounting expensive years' or decades' long studies as make-work schemes for medical scientists and their chums in Whitehall, Washington and elsewhere, the governments of the world might be better advised setting them to work to discover the actual causes of disease, and maybe to develop vaccines and other methods of combatting them, or better still, maybe they should follow in the footsteps of gerontologist Aubrey de Grey and his SENS organisation?"

Link: http://www.digitaljournal.com/article/311235

Source:
http://www.longevitymeme.org/newsletter/latest_rss_feed.cfm

Researchers are spending a fair amount of time on understanding why regeneration in mammals differs from - and is much worse than - regeneration in lower animals like salamanders. A salamander can grow back a limb any time it needs to, a mouse or a human not so much. But we can do the full regeneration trick to a far lesser degree, as humans and mice can both regrow the tip of a finger or toe when very young or very lucky, for example. You might also recall the MRL mice, an engineered species that can regenerate much more effectively than is normal for most mice.

One of the questions that researchers aim to answer is whether the mechanisms for salamander-like regeneration lie buried in mammalian biology, perhaps turned off for reasons involving cancer suppression. If they are there, perhaps they can be restored via drugs or genetic engineering for long enough to regrow major damage to limbs and organs. That's all speculative at this point, and looking more so after this latest research publication:

Tissue-specific adult stem cells are responsible for the ability of mammals to re-grow the tips of fingers or toes lost to trauma or surgery, say researchers at the Stanford University School of Medicine. The finding discredits a popular theory that holds that previously specialized cells regress, or dedifferentiate, in response to injury to form a pluripotent repair structure called a blastema.

"We've shown conclusively that what was thought to be a blastema is instead simply resident stem cells that are already committed to become specific tissue types," said Irving Weissman, MD, director of Stanford's Institute for Stem Cell Biology and Regenerative Medicine. "The controversy about limb regeneration in mammals should be over."

If you want to take the glass half full view, this might mean that it will be a shorter path to pushing these stem cells into doing more with less - rather than the alternative and longer path of trying to recreate salamander-like blastema behavior in mammals. But it's anyone's guess as to how much regeneration these cells are capable of if manipulated; no doubt less than we'd all like.

Source:
http://www.longevitymeme.org/newsletter/latest_rss_feed.cfm

When you're young, you expect to have a great deal of time ahead of you. You haven't spent much time yet, and so what remains seems like a fortune in comparison - enough to squander. Think of the way that wealthy children so often turn out despite the best efforts of their parents, their view of the value of money and economic common sense poisoned by having grown up with access to a great deal of money. But before you look down on them or pity them, think of your own situation with respect to the expected time remaining in your life. Your viewpoint on time, life, and the future was poisoned by having what appeared to be a great deal of remaining time, far more than it was easy to compare against what little you had lived to date ... so you valued time poorly.

We are evolved to squander the resources that shower upon us and gather in their piles, while spending a great deal of care, thought, and worry on resources that are scarce. So we care little about air, not so very much more about water, and not at all about time when we are young. But that stock of time diminishes as you grow old, and because there is less of it, it becomes more valuable. This is one reason why people are willing to spend greatly on medical technologies at the end of their lives - and here I am talking only of willingness, not any need to spend more. Aging brings with it degeneration and disease, and the cost of remaining alive and able to enjoy life accelerates with the passing years: the old spend increasingly more than the young because they have to in order to stay in the game. Note that "have to in order to stay in the game" is not the same thing at all as "willing to."

To be old is to live in in the mirror image of youth: time and no money has turned into money and no time. The value of money to an old person is typically less than it is to a young person, and that is nothing more than a measure of how much of the stuff you have: old people are typically much wealthier. The converse is true of remaining time, of which the young have a great deal, whilst the old are time-poor; thus the exchange rate between the time and money is radically different at the opposite ends of life. A young person will give away an hour to gain a small number of dollars, while an old person will spend ten times that sum to gain another hour. A cynic might suggest there is some form of arbitrage to found in this truth of human nature. If you like thinking along these lines, you might look back at past ruminations on the nature of wealth in a past post.

Time is everything. How much have time you spent reading this far? Could you have been doing something more useful, more optimal from your perspective? We make these small evaluations constantly, because time is the most valuable thing we have.

There are always people in the academic world who'd rather spend time looking at factors other than the obvious ones when it comes to aging and economic activity, of course:

Low opportunity cost, weak influence of quality of life in the face of death, the social value of life extension to others, shifting psychological reference points, and hope have been proposed as factors to explain why people apparently perceive marginal life extension at the end of life to have disproportionately greater value than its length. Such value may help to explain why medical spending to extend life at the end of life is as high as it is, and the various factors behind this value might provide normative rationale for that spending.

Upon critical analysis, however, most of these factors turn out to be questionable or incompletely conceived; this includes hope, which is examined here in special detail. These factors help to explain complexity and nuance in the normative issues, but they do not provide adequate justification for spending as high as it often is. In any case, two additional factors must be added to the descriptive explanation of high spending, and they throw its normative justification into further doubt: the "insurance effect" and provider-created demand. Overall, the perception of especially high value of life at the end of life provides some normative justification for high spending, but seldom strong justification, and not for spending as high as it often is.

The trouble begins with a person deciding that an entire clade of people are making systematically incorrect assessments of value despite having access to complete and correct data. Value is subjective, not objective, and it shouldn't be at all surprising that at the end of life there are radical shifts in the value placed by a dying person upon money and time. Note that I don't say "perceived value" - that phrase is just a subtle way of suggesting that the author is correct and the members of the clade are systematically wrong, which is in turn a subtle way of suggesting that value can be objective.

If you have bad or incomplete data, the value you ascribe will probably prove to be unhelpful if you act upon it, but it is still your subjective value: there is no "wrong" or "right" here, just a record of the outcome of a series of actions. People have a way of saying that you valued something wrongly if, by your actions based on that value, you manage to do yourself harm, economic or otherwise. But that really isn't a helpful way to look at subjective value: it is what it is, at any given moment. Either way, I'd argue that when it comes to life, longevity, and medical technology, there's a lot of reliance on bad and incomplete data taking place these days, given the possibilities presented by longevity science and the level of public ignorance of those possibilities. A fraction of people alive today will have the opportunity to live for centuries or longer, but consideration of that possibility is almost entirely absent from their economic calculations.

I suppose I should also mention that this short discussion has nothing much to say in connection with the horrible state of medical economics in the US. Participation in the heavily regulated marketplace for medical technology and services is a pit of horrors for both old and young: everyone suffers from the effects of regulation, lack of accountability for costs incurred, and the general miasma of government-induced systems failure. So arguments based on differential willingness to spend on medicine by age stand apart from that mess.

The neat endpoint to this post, if you want one, is that it can't hurt to think on the value you place on the time remaining in your life expectancy, and to look at whether you are basing both expectation and value on factual data.

Many of the worlds longest-lived people became the world's longest-lived people despite a history of what are considered to be poor lifestyle choices from the perspective of long term health. Amongst their number are smokers, the overweight, and the sedentary - all items shown to cause great harm to health in the long term. Studies have shown that each of these considered in isolation can shave as much as a decade from your life expectancy, and that's quite aside from what they will do to your quality of life via an increased risk of suffering chronic and debilitating medical conditions.

So how is it that we see a fair proportion of extremely old people with such a poor track record for basic good health choices over the course of their lives? So far it looks like that can be attributed to fortunate genes:

People who live to 95 or older are no more virtuous than the rest of us in terms of their diet, exercise routine or smoking and drinking habits ... Overall, people with exceptional longevity did not have healthier habits than the comparison group in terms of BMI, smoking, physical activity, or diet. For example, 27 percent of the elderly women and an equal percentage of women in the general population attempted to eat a low-calorie diet. Among long-living men, 24 percent consumed alcohol daily, compared with 22 percent of the general population. And only 43 percent of male centenarians reported engaging in regular exercise of moderate intensity, compared with 57 percent of men in the comparison group.

...

In previous studies of our centenarians, we've identified gene variants that exert particular physiology effects, such as causing significantly elevated levels of HDL or 'good' cholesterol. This study suggests that centenarians may possess additional longevity genes that help to buffer them against the harmful effects of an unhealthy lifestyle. ... Although this study demonstrates that centenarians can be obese, smoke and avoid exercise, those lifestyle habits are not good choices for most of us who do not have a family history of longevity. We should watch our weight, avoid smoking and be sure to exercise, since these activities have been shown to have great health benefits for the general population, including a longer lifespan.

Why rely on having a genetic buffer against subtle forms of self-harm when the odds are good that you have no such thing? The only reliable ways to ensure that you live for a long, long time in good health will come from progress in medical technology aimed at engineering greater human longevity: repair biotechnologies capable of reversing the known forms of cellular and molecular damage that cause aging. That progress in turn depends on the degree to which we choose to support and advocate rejuvenation research today.

Biomedical gerontologist Aubrey de Grey is one of the figures appearing in the documentary film "How to Live Forever." It's played straight but isn't a serious piece, as this review notes:

It's a huge subject, vital to every living person in the world - what it means to grow old and how one can cheat or at least postpone mortality. Fortunately, Mark S. Wexler eschews ponderousness in favor of a wry, observant, open-minded approach in his most informative and often quite funny documentary How to Live Forever. ... The film opens May 13 in New York followed by a national expansion May 22.

Still, there you have Aubrey de Grey in theater distribution (again) - and the more folk to hear his message, the better. It's still the case that the vast majority of people are not aware of the state of the art in longevity science, the near term potential for progress towards the repair of aging, and how to help make it all happen. For all the work of advocates over the years, this message remains insufficiently repeated and too quiet.

Another commentary is entitled "A Little More Fear of Death, Please?":

The title is something of a misnomer: with his mother gone, and himself on the downslope of 50, Mark Wexler makes a general study of life-extension experts, self-proclaimed and otherwise. ... Wexler's "wisest" friend, Pico Iyer, tells him that death's finality makes sense of life (for who?), but the director barely addresses the fear of death [and] his grief over the loss of a parent is neither as intense nor as personal as, say, Ross McElwee's in Time Indefinite. ... Wexler settles on the lasting resonance of art as mortality's consolation prize. ... His film, though, is a cutesy binder of folk remedies offering inadequate balm.

A little more fear of death indeed - a sentiment I endorse. What's not to fear about the downward slope of degeneration, increasing frailty, pain, suffering, and the calm madness of a world that accepts all this and does next to nothing about it?

There should be no such thing as "I don't know what to do with my life." Scratch that statement away and erase it, as it should be "I will aid the development of life extension technology until I do know."

It should be no surprise to anyone that many, or perhaps even a majority of people at any given time have no real idea as to what they want to do with their lives. No vision, no grand dream that captures them, no burning desire to achieve a specific great work. That isn't because they are incapable - far from it, it is because they haven't found their own personal blue touch paper yet. The space of ideas and ideals is vast, and even the most aggressively autodidactic internet-addicted polymath cannot embrace more than a fraction of the sphere of human knowledge. Yet you cannot know your grand vision, the one that resonates with everything your life has led to up until that point, if you never encounter its roots.

Which is where we come back to time. We tell the younger folk that it doesn't matter if they don't know what they want to do with their lives, as that knowledge will come with time. The rituals and mythology that spring from the passage from childhood to adulthood, repeated billions of times over the course of history, are as much about expanding horizons as they are about anything else. In our comparatively wealthy modern society, that process of expansion doesn't have to stop when you stop growing in body - except for the fact that we are all limited by the realities of the human condition, and aging in particular.

Our lives have a timer, and we are all well aware of it, for all that many of us prefer not to think about it at all. The whole structure of life and society revolves around the existence of that timer, as it ticks away the freedom we have remaining in which to find and work on something worthwhile. The rush to find meaning in life? There because we don't have enough time. The need to save for retirement and medical costs? The timer again, ticking away our health and ability to fend for ourselves.

When you cannot see even the first shape of what will be your life's work, and time is ticking away, the best thing you can do is to offer a helping hand to those who work on making more time - scientists, advocates, and others who support research and development of rejuvenation biotechnologies. You can do that at the same time as you search for the cause or idea that truly speaks to you, and it beats slumping back into the grey doldrums that seem to afflict so much of our society: people who never found that fire inside, and who have no time left in which to do so.

You have an option that the older folk of previous generations did not: you can help make more time for everyone, more health, more years, and time enough to find meaning in what you do.

All you need is love; love is just a game for two; we found love in a hopeless place is there anything that could be written about love that hasn't already been sung in the Top 40s chart?

Well, how about the health benefits of love? Generally, singers prefer songs about getting stronger after a break-up, but theres plenty of science to show that love and all the things that come with it are better for your health than being alone.

Love has the ability to powerfully influence our physical and mental wellbeing, explains Niels Ek, psychologist and co-founder of mental wellbeing and self-development platform Remente. Humans are typically social creatures and, often, we are strongest, healthiest, and happiest when we feel close to others.

An abundance of studies have found that loneliness negatively impacts our psychological wellbeing; it's associated with a higher probability of anxiety and depression. In contrast, research from the International Journal of Environmental Research and Public Healthsaw a positive correlation between relationships and mental health. Theycan, among other things, boost ones confidence and trust.

So, if you needed one more excuse to make that big romantic gesture this Valentines Day, heres a few bits of evidence to help your case

Well, at least when compared with being with other people. A study published by the American Psychomatic Medicine Society had 120 healthy adults wear blood pressure monitors for a six-day period. The research found that the participants systolic blood pressure was down by one point when they were with their partners, compared to when they were with other people.

This was even the case in participants who didnt describe their relationships as being particularly happy, suggesting familiarity and intimacy with another person is all it takes. Good to remember if your partner forgets your anniversary this year

As part of an attempt to promote marriage as a concept by George Bushs government, the US Health and Human Services Department reviewed a tonne of studies and found that those in long term relationships tended to visit doctors less and have shorter hospital stays.

It was unknown why this was, but it could be as simple as the idea that having a partner forces you to be healthy, says Ek. The health benefits are partly due to the camaraderie that comes with being involved with another person. A caring partner wants what is best for us and, therefore, tends to ensure that we eat, drink, and sleep as were supposed to, seek healthcare when we need it, and so on.

If youre annoyed at being expected to get a bunch of flowers for your partner on Valentines Day, just remember that youre actually helping yourself by doing so.

Thats according to a study published by the Association For Psychological Science. It starts by citing studies which have shown that higher life satisfaction leads to longevity, then goes on to present evidence showing that your partner having higher life satisfaction might also help boost longevity.

This could be down to the well-documented phenomenon where doing nice things for other people has been found to improve life satisfaction for the person doing the good deeds.

The early stages of a relationship can be stressful. You find yourself panicking about all manner of things: do they like me? Am I coming on too strong? Did I just blow it? Does my hair look good? Are they going to get on with my friends?

However, the evidence shows that after these initial doubts and worries youll generally become more relaxed, less anxious, and happier. A study from Harvard Medical School found that hugging, kissing, and sex with a partner releases a hormone called oxytocin, which deepens feelings of attachment as well as contentment, calmness, and security.

In addition, studies have shown that being around the person you love releases dopamine, the hormone responsible for feelings of happiness, and less release of cortisol, the hormone associated with stress.

Alright, alright, in the world of Tinder you dont need to be in love to have sex, but given the aforementioned study which found that sex with a partner boosts the release of oxytocin, it might be the ideal way of doing so. And doing it is exactly what you should be doing if you want to stay healthy.

A study from Wilkes University in Pennsylvania found that people who had sex once per week were 30pc higher in immunoglobulin A than in those who had no sex at all. And what does immunoglobulin A do? Well, it helps defend the body against illness.

However, its also worth noting that people who had sex more than twice per week were even lower in immunoglobin A than those who had no sex at all. And the study itself even stated that more research was probably needed before we could say definitely.

Originally posted here:
The health benefits of falling and staying in love - Telegraph.co.uk

You might recall that the Immortality Institute raised funds for a test of laser ablation of lipofuscin, to run on nematode worms using commercially available laser equipment:

The good news for today is that the longevity science grassroots centered at the Immortality Institute have successfully raised $8,000 to fund research into laser ablation of lipofuscin. Those funds will be matched up to $16,000 at the SENS Foundation and put towards work on a method of eliminating one form of damaging metabolic byproducts that build up with age.

Lipofuscin is the name given to a collection of various waste products of metabolism that are hard for the body to break down. They build up inside cells, collecting in the recycling mechanisms of lysosomes and causing cellular housekeeping to progressively fail over time. Ways to safely break down lipofuscin are very much required as a part of the envisaged package of future rejuvenation biotechnology that can prevent and reverse aging.

One proposed methodology for tackling lipofuscin is the use of pulsed laser light targeted at very specific molecules and molecular bonds: in theory, it should be possible to significantly impact lipofuscin levels without harming the cells that contain this gunk. Whether this is the case in practice remains to be seen, but it is an approach well worth testing: after all, lasers are already routinely used in dermatology to achieve conceptually similar goals, and the cost of this test is minimal in the grand scheme of things. Hence the laser ablation project funded by forward-looking donor and organized by the Immortality Institute.

You'll find recent updates on the state of the laser ablation test in the Longecity thread for the project:

Here is the basic agenda for the remainder of the project:

1) Test the effect of 8ns pulses on worm lifespan, at many different intensities. ... The beam coming straight out of the laser has terrific coherence and a nice tophat profile, which although it is 8ns, which is a little harsh, it is wonderfully consistent, great at destroying pigments, and we can rest assured that all worms on the slide are getting the exact same exposure every time.

2) Examine effect on worm activity/livelihood. Since the worms grow distinctively and progressively less active in the 2nd half of their life, this can be used to roughly assess quality of life changes; i.e. if worms are all dying at the same time, but at 75% lifespan, laser-treated groups are still quite active, this could be seen as a definite extension of useful lifespan.

3) Examine changes in pigmentation, if any. I may even be able to rig up a crude blacklight setup and get some fluorescence going. Or we could lop two months of the end of the 8-month project and buy a basic fluorescence scope with the extra $2500

...

4) Assess the effect of laser treatment on a more long-lived strain of worms (such as DAF-16 mutants), as well as the wild-type. This could provide useful clues as to what is going on, whichever way the results go.

...

It's still taking awhile to breed more DA1116 worms. I can see how this is going to go - things are going to stretch out a bit, partly due to my schedule and partly due to using long-lived worms, and the nature of lifespan experiments in general. Therefore I propose using experiments as milestones instead of sticking to a fixed weekly or monthly schedule. Thus the project will span at least 8 complete lifespan experiments, regardless of how long it takes to complete them. The remaining 'monthly' salary and expense checks could be sent at the start of experiments 3, 5 and 7 - which will doubtless end up being more than one month apart. This definitely seems more appropriate to me - that way all of our gracious donors get the same amount of science for their money, regardless of how long it takes.

The fluorescence scope may or may not be purchased for this project, depending on how our financial situation pans out on this end. It may end up being budgeted as part of a future project proposal instead; but we can cross that bridge when we get there.

I'll let everyone know as soon as the worm zapping begins.

One of the Immortality Institute volunteers visited the lab recently, and so you'll find photographs of the equipment, work area, and researcher in the thread to go along with the updates.

By way of a reminder, the Institute continues to raise funding for their next project, an investigation of microglia transplantation as a therapy for age-related neurodegeneration. $5,500 of the needed $8,000 has been raised, and futher donations are very welcome. Every dollar donated will be matched by an additional dollar from the Institute and its sponsors, so that the completed fundraiser will send $16,000 to the laboratory that will carry out the research:

Cognitive functions of the brain decline with age. One of the protective cell types in the brain are called microglia cells. However, these microglia cells also loose function with age. Our aim is to replace non-functional microglia [in mice] with new and young microglia cells derived from adult stem cells.

...

The full PDF format research proposal is available: the work will be carried out by a graduate research assistant and will cost $16,000. This is the essence of our present era of biotechnology: a task that would have occupied a whole laboratory and its equipment in the 1980s, and cost a great deal of money if it was even possible at all, is now something that a skilled graduate-level life scientist can organize and run himself within an established lab.

The Methuselah Foundation invests in a variety of companies, and one of them is Silverstone Solutions. Here the Foundation notes a demonstration of the company's product: "In what is the largest single-hospital kidney swap in the history of California, five patients received five kidneys from healthy donors in a marathon series of operations on Friday, April 1st 2011 ... 'Paired donation' is the procedure that makes it possible, a relatively new phenomenon in transplantation surgery that allows for a live kidney going to someone who has a friend or relative willing to donate an organ not compatible for them but a match for someone else. The donor matches one who needs a kidney and that patient's incompatible donor matches someone else and so on, like a chain. ... Imagine that - multiple lives being extended in one fell swoop! This is one of many reasons why Methuselah Foundation has proudly invested in Silverstone Matchmaker, a break-through computer software that makes the pairings possible. It quickly computes the myriad of possible matches in a pool of prospective donors and recipients, minimizing time and effort that the transplant center needs to reach this goal. ... That is why we proudly extend an angel financing arm, funding the development of the bleeding-edge improvements to the Silverstone technology called MatchGrid. This event is in keeping with Methuselah Foundation's strategy of making investments in life-extending technologies that work RIGHT NOW (dangit!) and that also have long term positive implications for general life extension in the tissue engineering realm. Our long term vision for this technology? We hope that its massive and super performance data management system will eventually play a role in the an envisioned 'Postscript' language that can send printing instructions for creating new tissues and eventually organs to be used by tissue printers such as Organovo's sci-fi worthy 3D tissue printer, another founding angel investment by you, the donors of Methuselah Foundation."

http://blog.methuselahfoundation.org/2011/04/hot_dog_a_record-breaking_5-transplant_kidney_swap.html

Over at Depressed Metabolism, you'll find a review of The Future of Aging, a book that covers the high points of longevity research and development pretty much from end to end. That includes viewpoints on transhumanist ideals of an ageless society, present work on rejuvenation biotechnology, the cryonics industry, as well as mainstream work on understanding calorie restriction and slowing aging through metabolic manipulation.

Editor-in-chief, cryobiologist, and aging researcher Gregory M. Fahy and his associate editors Michael D. West, L. Stephen Cole and Steven B. Harris have compiled what might be the most impressive collection of articles on interventive gerontology to date in their 866 page collection The Future of Aging: Pathways to Human Life Extension. The book is divided into 2 parts. The first part includes general, scientific, social and philosophical perspectives on life extension. The second part is a collection of proposed interventions, which are organized in chronological order, starting with the (projected) earliest interventions first. Of course, such an organization of the materials necessitates a subjective estimation of when such technologies will be available and is bound to be controversial. The collection closes with a number of appendices about contemporary anti-aging funding and projects (SENS, Manhattan Beach Project).

I wanted to draw your attention to this line of thinking:

One thing that remains a mystery to me is how such an accelerating pace of anti-aging technologies could be validated considering the relatively long life expectancy of humans. Presumably we are expected to adopt a lot of these technologies based on their theoretical merits, success in animal studies, or short-term effects in humans. ... Reading all these inspiring examples, however, I found myself faced with the same kind of despair as when reading about all the neuroprotective interventions in stroke and cardiac arrest. There is great uncertainty how such interventions would fare in humans (or other animals) and, more specific to the objective of human life extension, how we ourselves can ascertain that there are no long-term adverse consequences. ... As reiterated throughout this review, the gold standard and most rigorous determination of the efficacy of anti-aging therapies and interventions is to empirically determine whether they increase maximum human lifespan.

Everyone alive today who ultimately has the chance to benefit from future rejuvenation medicine or methods to significantly slow aging will be using what is at first essentially unproven technology. It will be developed with the best knowledge and insight of the time, but proof is a very high bar when reaching the gold standard involves waiting for decades after the introduction of new therapies. We have a very good grasp of what should extend life and reverse the damage of aging in humans, and it is simply not an option to hold off to see if the first generation of therapies based on this knowledge do in fact extend life in humans. Just as is the case for the practice of calorie restriction today, we will adopt - and are best served by adopting - the use of those technologies that early on in their development can demonstrate (a) extended life in mice, (b) impressive short term changes in the biochemistry of humans, and (c) an acceptable level of observed side-effects and safety.

This all very reasonable given the circumstances: we lack the luxury of time. Facing the choice between calculated risk and the certain suffering that leads to death, sane people will choose risk. Unfortunately, fighting for the right to be able to take that risk - both in medical development and in the use of the resulting biotechnologies - is very necessary, given the present regulatory environment:

Looking back from the perspective of 2035, I guess we should all be surprised that it took so long. The Vegas Group came together formally sometime in 2016, though the first kick-off meeting was the year prior at one of the bi-annual conventions for longevity research held in California. By that time, more than a dozen gene manipulations and other biotechnologies had been shown to significantly extend life in mice, but no progress was being made to develop these technologies for human use. The Vegas Group was a natural outgrowth of a decade of advocacy and anticipation for human enhancement technologies, coupled with the frustrating realization that no such technologies would be meaningfully developed, never mind made available to the public, under the regulatory regimes then in place in the US and Europe.

There were initial fractures in the Vegas Group around the course of political change versus direct action - which led to the formation of another influential movement discussed elsewhere - but by 2017 the direct action contingent of the Vegas Group consisted of about a hundred people all told. Their declared objective was a distributed collaborative effort to (a) develop human versions of the most successful longevity and metabolic enhancements demonstrated in mice, and (b) cultivate hospitable medical groups in the Asia-Pacific countries. When these technologies were developed, the founding members would cast lots and carefully test upon themselves, in rotation, and through the agency of medical centers in Asia. In doing this the hope was to spur change in the public view and greater progress in the commercialization of these technologies - and of course to gain access to manipulations that were greatly extending life in mice.

Interesting research reported via ScienceDaily: "Unexpected results from a [recent study] could completely alter scientists' ideas about Alzheimer's disease - pointing to the liver instead of the brain as the source of the 'amyloid' that deposits as brain plaques associated with this devastating condition. The findings could offer a relatively simple approach for Alzheimer's prevention and treatment. ... The product of [the mouse gene corresponding to a gene known to predispose humans carrying particular variations of it to develop early-onset Alzheimer's disease], called Presenilin2, is [involved] in the generation of pathogenic beta amyloid. Unexpectedly, heritable expression of Presenilin2 was found in the liver but not in the brain. Higher expression of Presenilin2 in the liver correlated with greater accumulation of beta amyloid in the brain and development of Alzheimer's-like pathology. ... This finding suggested that significant concentrations of beta amyloid might originate in the liver, circulate in the blood, and enter the brain. If true, blocking production of beta amyloid in the liver should protect the brain. ... mice were administered imatinib [which] has poor penetration of the blood-brain barrier in both mice and humans. ... Because it doesn't penetrate the blood-brain barrier, we were able to focus on the production of amyloid outside of the brain and how that production might contribute to amyloid that accumulates in the brain, where it is associated with disease. ... the drug dramatically reduced beta amyloid not only in the blood, but also in the brain where the drug cannot penetrate. Thus, an appreciable portion of brain amyloid must originate outside of the brain, and imatinib represents a candidate for preventing and treating Alzheimer's."

Link: http://www.sciencedaily.com/releases/2011/03/110303134435.htm

Via EurekAlert!: "A gene therapy called NLX-P101 dramatically reduces movement impairment in Parkinson's patients, according to results of a Phase 2 study ... The approach introduces a gene into the brain to normalize chemical signaling. ... The study is the first successful randomized, double-blind clinical trial of a gene therapy for Parkinson's or any neurologic disorder ... Half of patients receiving gene therapy achieved dramatic symptom improvements, compared with just 14 percent in the control group. Overall, patients receiving gene therapy had a 23.1 percent improvement in motor score, compared to a 12.7 percent improvement in the control group. ... Improved motor control was seen at one month and continued virtually unchanged throughout the six-month study period. ... Gene therapy is the use of a gene to change the function of cells or organs to improve or prevent disease. To transfer genes into cells, an inert virus is used to deliver the gene into a target cell. In this case, the glutamic acid decarboxylase (GAD) gene was used because GAD makes a chemical called GABA, a major inhibitory neurotransmitter in the brain that helps 'quiet' excessive neuronal firing related to Parkinson's disease. ... In Parkinson's disease, not only do patients lose many dopamine-producing brain cells, but they also develop substantial reductions in the activity and amount of GABA in their brains. This causes a dysfunction in brain circuitry responsible for coordinating movement."

Link: http://www.eurekalert.org/pub_releases/2011-03/nyph-gtr031411.php