Politics, perceptions, and money: these are the guiding trinity of research at the grand scale, the source of determinants for the work of thousands of researchers and the rate and direction of progress in broad fields of medical science - or so says the author of this article on the state of longevity science:

It has been clear for many years that the rate of aging is malleable in diverse species, and the discovery in 2009 that a drug called rapamycin can extend maximum life span in mice suggested that it's now technically feasible to develop anti-aging agents that really work as advertised. Unfortunately, I see no commercial interest in doing so.

The focus here is the mainstream of research, aimed at slowing aging by metabolic manipulation. This, as you all know by now, is the slow boat to nowhere in my view. The only practical way ahead that seems plausible to produce meaningful rejuvenation of the old in our lifetimes is some variant of SENS, the Strategies for Engineered Neligible Senescence: focus on repair and reversal of damage, not on slowing down the rate at which damage accrues. Repair is no harder, and arguably an easier path, and the end result will be far more effective in terms of years gained and suffering quashed. But SENS and other repair strategies yet to emerge into a coherent research program are the minority view in the field, still working to attain recognition and funding - bear that in mind when you read about the hurdles that groups with far more credit in the scientific community are struggling with. It's a long way from here to where we need to be, and there are two battles yet to win: firstly to persuade the research community to adopt the better strategic direction that SENS represents, and secondly to persuade some fraction of the world that reversing aging through biotechnology can and should be achieved within a matter of a few decades.

But back to the article:

Prominent advisors to the National Institute on Aging, as well as some of its officials, are enthusiastic about anti-aging drugs' huge potential to improve public health. In fact, a few years ago the NIA's founding director, the late Robert N. Butler, joined three visionary gerontologists to urge that the federal government mount a major program to accelerate development of such medicines, including funding for clinical trials and the preclinical research needed to make them feasible.

But the idea of investing taxpayer dollars in such a program has proved a very hard sell. As gerontologist Richard A. Miller once put it, "A president who announces a war on cancer wins political points, but a president who publicly committed the government's resources to research on extending people's life span would be deemed certifiable."

Which gets us to the root problem: Few people - including policymakers and medical experts who advise them - appear to realize that the ability to brake aging is now within our grasp, and that even modestly effective anti-aging drugs promise the biggest gains in public health since the advent of vaccines and antibiotics nearly a century ago. Indeed, I suspect most people still regard aging as an inalterable part of the human condition - a view reinforced by the fact that pharmaceutical companies just say no to anti-aging drug development.

An important line item that the author omits is that Big Pharma - and a hundred biotech startups, if there were any justice in the world - don't engage in longevity science because the FDA will not approve therapies for aging, and indeed could not possibly ever approve therapies for aging under its present regulatory regime. There is no way to sell to the clinics in the US marketplace, so there is no potential profit for US-based developers, so there is next to no venture funding for development of promising longevity science. Politics, perceptions, and money - and it's the political and regulatory establishment that is the biggest roadblock here.

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

Reactive oxygen species (ROS) are damaging molecules that can rip up important cellular machinery; all machinery in a cell is an arrangement of atoms, and promiscuously reactive molecules can gum up the works, pull out important parts of the machinery, and otherwise cause all sorts of issues. In discussions of our biology, the term free radical is often used interchangeably to refer to these reactive molecules. They are produced within our cells as a byproduct of some of the most important mechanisms of metabolism, a fact shared by the vast majority of species, dating back far into evolutionary time. As for all aspects of cellular chemistry with such deep origins, evolution has has a very long time indeed in which to build feedback loops and interlaced machinery that depend upon the existence of ROS, co-opting these molecules for diverse purposes in signaling and regulating the operation of cells and tissues.

Thus ROS generation and damage is not just a harmful side-effect of being alive and having cells that are churning away, but it is also fundamental to the complex processes by which our metabolism maintains cellular homeostasis in the face of day to day challenges. Here are a couple of open access papers that summarize what is known about the more important roles of ROS in the body - in the first paper, section 6 is where you'll find the focus on aging, while the second paper looks at the intersection of muscle, ROS, and exercise.

Mitochondria-Ros Crosstalk in the Control of Cell Death and Aging

ROS are a normal side product of the respiration process, and they react with lipids, protein, and DNA, generating oxidative damage. Indeed, mitochondria are the major site of ROS production, but also the major targets of their detrimental effects, representing the trigger for several mitochondrial dysfunctions. In this review, we will focus on this deadly liaison, with particular attention on ROS production, mitochondrial ROS targets, and their role in apoptosis, autophagy, and aging. ... At physiological levels, ROS function as 'redox messengers' in intracellular signalling and regulation, whereas excess ROS induce cell death by promoting the intrinsic apoptotic pathway. Recent work has pointed to a further role of ROS in activation of autophagy and their importance in the regulation of aging. This review will focus on mitochondria as producers and targets of ROS and will summarize different proteins that modulate the redox state of the cell. Moreover, the involvement of ROS and mitochondria in different molecular pathways controlling lifespan will be reported, pointing out the role of ROS as a 'balance of power,' directing the cell towards life or death.

...

The decline associated with aging is caused by the accumulation of ROS, as supported by cellular and biological data from different model systems and organisms. Indeed defects in antioxidant defense mechanisms fail to protect against oxidative damage, reducing lifespan and causing cardiomyopathy, neurodegeneration, and cancer. ... The relationship between mitochondria dysfunctions observed during aging and ROS production is still debated. However, it is clear that the decline of the integrity of mitochondria as a function of age is implicated in aging and age-related diseases.
Given this wide scientific evidence, many studies were aimed to identify the molecular mechanisms responsible for ROS deleterious effects on the aging process.

Reactive Oxygen Species in Skeletal Muscle Signaling

Up to the 1990s of the past century, ROS have been solely considered as toxic species resulting in oxidative stress, pathogenesis and aging. However, there is now clear evidence that ROS are not merely toxic species but also - within certain concentrations - useful signaling molecules regulating physiological processes. During intense skeletal muscle contractile activity myotubes' mitochondria generate high ROS flows: this renders skeletal muscle a tissue where ROS hold a particular relevance. According to their hormetic nature, in muscles ROS may trigger different signaling pathways leading to diverging responses, from adaptation to cell death.

...

As an example, many studies have concluded that inactivity-induced ROS production in skeletal muscle contributes to disuse muscle atrophy. On the contrary, growing evidence also suggests that intracellular ROS production is a required signal for the normal remodelling that occurs in skeletal muscle in response to repeated bouts of endurance exercise. How can the same trigger promote such opposite effects? Based upon current knowledge, it appears that the mode and the situation characterizing skeletal muscle cells exposure to ROS may account, at least in part, for this apparent paradox. Transiently increased, moderate levels of oxidative stress might represent a potentially health-promoting process, whereas its uncontrolled persistence and/or propagation might result in overwhelming cell damage thus turning into a pathological event: for instance, the role of ROS in inflammation fits well with this model.

...

Supplementation with exogenous antioxidants is being widely studied to attain and maintain an 'ideal titration' of ROS within skeletal muscle: unfortunately, at the present, no clear indication of the benefits arising from supplemental antioxidant intake emerges from literature.

The evolution of knowledge regarding ROS in human metabolism, and the parallel evolution of the market for dietary antioxidant supplements, should be taken as a cautionary tale. Metabolism is complicated, and trying to alter its operation through the use of such blunt tools is probably not the most efficient way to use science to extend human life.

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

One of the ways in which general health practices - such as exercise and fitness - steer cognitive health is through the state of the blood vessels in your brain: if they are deteriorating more rapidly, then more microinfarcts will occur, destroying more of the function of the brain, one tiny piece at a time. This is a mechanism quite distinct from the root causes of dementias like Alzheimer's disease, as this study illustrates: "This study was untaken to investigate the association of micro brain infarcts (MBIs) with antemortem global cognitive function (CF). ... Subjects were 436 well-characterized male decedents from the Honolulu Asia Aging Autopsy Study. Brain pathology was ascertained with standardized methods, CF was measured by the Cognitive Abilities Screening Instrument, and data were analyzed using formal mediation analyses, adjusted for age at death, time between last CF measure and death, education, and head size. Based on antemortem diagnoses, demented and nondemented subjects were examined together and separately. ... In those with no dementia, MBIs were strongly associated with the last antemortem CF score ... This suggests that microinfarct pathology is a significant and independent factor contributing to brain atrophy and cognitive impairment, particularly before dementia is clinically evident. The role of vascular damage as initiator, stimulator, or additive contributor to neurodegeneration may differ depending on when in the trajectory toward dementia the lesions develop."

Link: http://www.ncbi.nlm.nih.gov/pubmed/22162060

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

Opposition to enhanced human longevity, which often advocates collectivism and the use of government force to prevent other people from extending their lives through biotechnology, is based on a range of factors: fear of change, the green-eyed monster of envy (who has set up shop in the environmentalist movement these days), and ignorance of basic economics. In the latter case, some folk naively believe all resources to be limited - jobs, wealth, and so forth - rather than growing with population and length of life. But all of these things are made by people, and the more people there are and the longer those people live in good health, the more creation will take place. But there are always naysayers who have convinced themselves that a hundred thousand deaths due to aging every day and the ongoing suffering of hundreds of millions is necessary because of their own vague and unrealized anxieties about the future. Here is one example: "Wolpe's own perspective is that our drive toward immortality is basically selfish. He sees few benefits to society, and a good deal of potential harm, in our living to 200 or beyond. ... There is a natural wisdom in replacing us. There's a natural wisdom in the idea that new people who arise in new circumstances have new perspectives on the world. ... Look at the generations living now from the World War II generation to the Baby Boomers, to Gen-X, all the way down. The young generation today, the people in their teens and 20's today were steeped in a different brine than I was as a Baby Boomer. They were brought up with technology at their fingertips. They move naturally and easily through that world. And the idea that if I got to live to, you know, 150 or 200, that that would be a good thing for anyone other than me, I think is a misguided notion. And there's a deep selfishness in the move towards immortality and these people like Aubrey de Grey and others who are really looking for that Fountain of Youth. ... If we don't change, for example, reproduction, if reproduction stayed between let's say, 20 and 40, that means that you would have another 80 years after reproducing that you'd be around. So there's even the question of how we're going to restructure the human lifespan. Is that a proper dynamic to have your children and then live another hundred years?" As usual, this is airy nonsense when held up against the reality of the vast and pervasive suffering caused by aging - suffering that we can work to address instead of just waffling about intangibles.

Link: http://bigthink.com/ideas/41527?page=all

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

Below you'll see optimism on the topic of longevity and the future, personal and otherwise, from the establishment political press, which is an unusual enough event to be worthy of remark. These are well-written general interest articles that don't look far beyond a high level overview of economics and exercise, so your mileage may vary - they don't touch on any of the more earnest scientific work on aging and rejuvenation such as SENS, for example. But take a look and see what you think:

Longevity: a Manual

"Genes account for one-fourth to one-third of longevity," estimated Howard Friedman, a professor of psychology at the University of California (Riverside) and the coauthor of The Longevity Project, published this year. "That leaves well over half not accounted for."

Most of the rest, for better or worse, is up to you. "The importance of choices people make is in so many ways responsible for the quality of life in old age," said Charles Reynolds III, a professor of geriatric psychiatry, neurology, and neuroscience at the University of Pittsburgh medical school. "Many people think they should be entitled to a good-quality 25 years after age 60. Well, they're not necessarily entitled, but they can put the odds in their favor."

One way - "the least speculative and the most obvious" - is with exercise, according to Simon Melov, a Buck Institute biochemist. "More activity is better than no activity, and most people are not doing anything. They're just sitting there." Exercise, he said, reduces the risk of cardiovascular disease and perhaps even a decline in cognition. One needn't run a marathon. Gardening, walking, swimming, woodworking - all of these are more active than just sitting.

No, Malthus, No: Living Longer Is a Blessing, Not a Curse

Long life may well be a blessing for the individual. But is it also a blessing for society? The fashionable answer is an increasingly anxious no. Choose your apocalyptic metaphor. The aging of America represents a "financial time bomb," The New York Times has proclaimed - with the solvency of Social Security, Medicare, and Medicaid (the last in line for nursing-home payments for patients who have depleted their assets) all at risk. Foreign Policy magazine has warned that a "gray tsunami is sweeping the planet," the United States included.

And yet the forecast that Americans' increased longevity is a collective downer for the nation ain't necessarily so. The fiscal threat, while real, provides too narrow a prism for understanding a question so complex. History suggests that the size of the total economic pie tends to grow larger as life expectancy rises. From 1950 to 2010, Americans' life expectancy at birth grew by 15 percent and, at age 65, by more than 30 percent - even as household incomes and the gross domestic product increased sixfold.

So, as counterintuitive as this may sound, it is possible, even likely - listen up, worrywarts! - for Americans to live longer and grow richer.

In fact the weight of evidence points strongly towards longevity and wealth moving hand in hand, influencing one another. People with longer time horizons make better decisions for the stewardship of resources, while at the same time increasing wealth means better medicine - more research, improved medicine, greater ability to purchase medical services, and so forth. See these items from the Fight Aging! archives, for example:

• Wealth and Longevity
• Longevity Tends to Change Economic Behavior for the Better
• What is Wealth?
• A Visualization of Wealth and Heath Over Time

Arguing against this view on the basis of the evidence is actually a pretty steep cliff to climb (not that that seems to stop the naysayers). Empires fall and regions become poor for all sorts of reasons, and the US is on the way to a sad end itself, but increasing life expectancy and growth in wealth are not amongst the causes.

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

A progressive build up of advanced glycation end products (AGEs) is implicated in the aging process; they contribute to skin aging, for example. There are some research programs aimed at producing drugs or other treatments to break down the important AGEs in humans, but far too few of them, and poorly funded. Here, researchers look at AGEs in a mole rat species: "Mole-rat of the genus Fukomys are mammals whose life span is strongly influenced by reproductive status with breeders far outliving nonbreeders. This raises the important question of whether increased longevity of the breeders is reflected in atypical expression of biochemical markers of aging. Here, we measured markers of glycation and advanced glycation end-products formed in insoluble skin collagen of Ansell's mole-rat Fukomys anselli as a function of age and breeding status. Glucosepane, pentosidine, and total advanced glycation end-product content significantly increased with age after correction for breeder status and sex. Unexpectedly, total advanced glycation end-products, glucosepane, and carboxymethyl-lysine (CML) were significantly higher in breeders versus nonbreeders suggesting that breeders have evolved powerful defenses against combined oxidant and carbonyl stress compared with nonbreeders. Most interestingly, when compared with other mammals, pentosidine formation rate was lower in mole-rat compared with other short-lived rodents confirming previous observations of an inverse relationship between longevity and pentosidine formation rates in skin collagen."

Link: http://www.ncbi.nlm.nih.gov/pubmed/22156473

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

Correlations between character traits and longevity seem to be a growing area of study; interesting results, though of dubious importance, I think: "The relationship between personality and life span is not well understood, and no study to date has examined genetic influences underlying this relationship. The present study aimed to explore the phenotypic and genetic relationship between personality and life span, as well as genetic influences on all-cause mortality. ... Prospective community-based study including 3752 twin individuals older than 50 years. Neuroticism, psychoticism, extraversion, and social desirability and pessimism/optimism were measured at baseline using the Revised Eysenck Personality Questionnaire and the Revised Life Orientation Test, respectively. Information on age at death was obtained 16 years after the initial assessment of personality. ... Extraversion was inversely related to mortality with the risk of death decreasing 3% per unit increase of the extraversion score. Psychoticism and pessimism were positively related to mortality with a 36% and 39% increase in risk of death per unit increase in the respective personality score. Heritability of life span was 7%. ... Extraversion, psychoticism, and optimism/pessimism are significant predictors of longevity; extraversion is associated with a reduction, and pessimism and psychoticism are associated with an increase in mortality risk. Genetic influences on longevity in Australian twins are very low (7%). Our data also suggest a small, albeit nonsignificant, genetic influence on the relationship of pessimism and psychoticism with life span."

Link: http://www.ncbi.nlm.nih.gov/pubmed/22155943

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

I noticed an easy read of an open access position paper today that asks whether the common wisdom regarding the prevalence of age-related disease today is an open and shut case. Can we definitively say that, in comparison to our ancestors, we are not just living longer and are generally far wealthier, but are also suffering higher rates of cancer, cardiovascular disease, diabetes, and other chronic diseases suffered at the end of life? The general consensus as presented by the media and onlookers is that yes, it's an epidemic - really a terrible misuse of the word, since these age-related conditions are not infectious in nature - and there you have it. But here's a counterpoint:

Over the last 110 years, average global life expectancy has more than doubled from 31 years of age to 65 years of age. This trend is expected to continue, and many of the children born after the year 2000 can expect to live to celebrate their hundredth birthday. In the last 20 years alone, average life expectancy has increased globally by 6 years.

During the same period, doctors have announced a global epidemic of the most common killers: cardiovascular disease, diabetes, chronic kidney, and chronic obstructive pulmonary disease. One of the most important reasons for the more frequent recognition of these diseases is the fact that their diagnostic criteria have changed and become much more acute during the past few years.

These changes in diagnostic criteria have made it difficult, or even impossible, to compare the present statistical data regarding these diseases to historical data for the same illnesses. Due to this difficulty, there is no evidence-based comparison of the prevalence of any disease at present and in the past. Before announcing a global epidemic, a fair epidemiological comparison should be made, based upon the same definitions and using identical diagnostic tools.

In essence this is an argument based on the challenge of distinguishing between the consequences of longevity upon risk and levels of age-related disease and the effects of increasing wealth and improved medical technologies upon diagnosis rates. If you have more money and better medicine, you are more likely to be diagnosed, treated, and entered into the records than otherwise. Following this argument to its conclusion suggests that the effects of increasing wealth and longevity on disease rates are in fact lower than the raw data would imply, and that this effect will always be present in an age of improving technology and increasing wealth.

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

Via EurekAlert!: [Researchers] have developed a jelly-like material and wound treatment method that, in early experiments on skin damaged by severe burns, appeared to regenerate healthy, scar-free tissue. ... the researchers reported their promising results from mouse tissue tests. The new treatment has not yet been tested on human patients. But the researchers say the procedure, which promotes the formation of new blood vessels and skin, including hair follicles, could lead to greatly improved healing ... the hydrogel is constructed in such a way that it allows tissue regeneration and blood vessel formation to occur very quickly. ... Inflammatory cells are able to easily penetrate and degrade the hydrogel, enabling blood vessels to fill in and support wound healing and the growth of new tissue ... For burns, the faster this process occurs, [the] less there is a chance for scarring. Originally, [the] team intended to load the gel with stem cells and infuse it with growth factors to trigger and direct the tissue development. Instead, they tested the gel alone [and] were surprised to see such complete regeneration in the absence of any added biological signals. ... The hydrogel is mainly made of water with dissolved dextran, a polysaccharide (sugar molecule chains). ... It also could be that the physical structure of the hydrogel guides the repair .. [Researchers speculate] that the hydrogel may recruit circulating bone marrow stem cells in the bloodstream. ... It's possible the gel is somehow signaling the stem cells to become new skin and blood vessels."

Link: http://www.eurekalert.org/pub_releases/2011-12/jhu-itb121311.php

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

The use of nanoparticles to precisely deliver compounds to cells and specific locations within cells has a far broader application than just cancer therapies. Any existing drug that can be targeted this way can be made far more effective: provided in much smaller doses and with greatly reduced side-effects. For example: "Hitching a ride into the retina on nanoparticles called dendrimers offers a new way to treat age-related macular degeneration and retinitis pigmentosa. A study [shows] that steroids attached to the dendrimers target the damage-causing cells associated with neuroinflammation, leaving the rest of the eye unaffected and preserving vision. ... There is no cure for these diseases. An effective treatment could offer hope to hundreds of millions of patients worldwide. ... [Researchers] tested the dendrimer delivery system in rats that develop neuroinflammation. The target was microglial cells, inflammatory cells in charge of cleaning up dead and dying material in the eye ... When activated as 'trash collectors,' the cells cause damage via neuroinflammation - a hallmark of each disease. The microglial cells gobble up the dendrimers, and the drug then shuts down the cells' activity. ... Surprisingly, the activated microglia in the degenerating retina appeared to eat the dendrimer selectively, and retain them for at least a month. The drug is released from the dendrimer in a sustained fashion inside these cells, offering targeted neuroprotection to the retina. ... The treatment reduced neuroinflammation in the rat model and protected vision by preventing injury to photoreceptors in the retina. Though the steroid offers only temporary protection, the treatment as a whole provides sustained relief from neuroinflammation."

Link: http://www.eurekalert.org/pub_releases/2011-12/mc-nhm121311.php

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