FIGHT AGING! NEWSLETTER
April 16th 2012
The Fight Aging! Newsletter is a weekly email containing news, opinions, and happenings for people interested in aging science and engineered longevity: making use of diet, lifestyle choices, technology, and proven medical advances to live healthy, longer lives. This newsletter is published under the Creative Commons Attribution 3.0 license. In short, this means that you are encouraged to republish and rewrite it in any way you see fit, the only requirements being that you provide attribution and a link to Fight Aging!
- SENS5 Video: Increased Damage to Proteins in Aging
- Revisiting Resveratrol and the Big Red Lever
- From the Mainstream: Old Age is not for Sissies
- No Genetic Longevity-Cancer Balance for Humans?
- Latest Headlines from Fight Aging!
SENS5 VIDEO: INCREASED DAMAGE TO PROTEINS IN AGING
Another video from the SENS5 conference is posted online:
"At its simplest, aging is nothing more than damage and the flailing of adaptive systems that try and fail to cope with operating while damaged. The damage of aging comes in a variety of forms, but much of it involves broken proteins. Proteins are the cogs and wheels of cellular machinery, intricate assemblies of atoms encoded in your DNA and tailored by evolution to specific roles. The inside of any cell is a madhouse of flowing material and chemical reactions, however, not all of them benign. There is constant turnover as proteins are damaged, recycled, and replaced, some more often than others. In this dynamic environment of wear and repair, it takes decades for forms of damage to begin to overwhelm the recycling machinery, but the downward slide only gets faster with time."
REVISITING RESVERATROL AND THE BIG RED LEVER
The hype machines that accompany research that produces something the supplement industry can latch onto and sell are predictable. Don't fall for it next time:
"Our metabolic biochemistry looks like a big wall full of levers. Some of them are painted red, and we think we understand what the instructions beneath these red levers say. Maybe. How much information do you feel you would like before you pull the big red levers in your own personal metabolism? What level of risk due to disease would you presently need to be suffering in order to take the risk represented by a new compound? How do you evaluate these levels of risk?
"Resveratrol has turned out, almost predictably, to be another heaped mound of hype that buries a modest kernel of interesting-but-not-terribly-applicable metabolic research. At this stage it seems fairly certain that resveratrol does not extend life in mammals to any great degree - when you find compounds that can do that, there is little uncertainty once the life span studies are in and replicated. See the past couple of years of work on rapamycin in mice as a contrasting example to the uncertainty and lack of verifiable effects for resveratrol and its derived compounds.
"The sensible thing to do whenever another of these oral-fixation ingested substance hype machines emerges from the juncture of the scientific and business worlds is to balance the purported results against the clear, proven, and solid benefits of exercise and calorie restriction. The risks in moderate exercise and calorie restriction are minimal, while the evidence for great benefit to long-term health is gold-plated and voluminous. When someone is trying to convince you to spend money on something that seems unlikely to produce even a pale shadow of the health benefits of either exercise or calorie restriction, and has largely unknown long term risks - then why even try? It just doesn't make sense.
"The research community, and just as importantly the public at large, needs to move beyond their enthusiasm for metabolic manipulation through ingested substances as a path to extending healthy life. It's a grand example of looking for the lost keys under the lamp post - doing something just because it's easier and the path of least resistance, regardless of the likelihood of significant results at the end of the day. Real progress towards longer lives is only going to come through building medical technology capable of repair and rejuvenation at the level cells, organs, and systems within the body: very specific biotechnologies engineered to perform very specific jobs within and around cell structures, and aim to exactly reverse aging by doing so. That couldn't possibly be further removed from the present dominant strategy of mining the natural world for compounds that might or might not cause more minor benefits than minor disadvantages."
FROM THE MAINSTREAM: OLD AGE IS NOT FOR SISSIES
A piece from the heads of the Alliance for Aging Research and the Buck Institute for Research on Aging:
"Bette Davis was right - old age is not for sissies. One hundred years ago most of us didn't have the luxury of old age. Today, life expectancy is almost 80 years. But while we've gotten very good at adding life-years, we've yet to master how to keep those years healthy and vigorous. Eighty percent of seniors have at least one major chronic condition and half have two or more. Chronic diseases of later life are costing the nation more than $1 trillion per year - a figure expected to increase to $6 trillion by the middle of this century.
"Scientists who study aging are in general agreement that the process isn't set in stone - the aging process can be sped up by genetics or poor lifestyle choices, but it can also be slowed down. With sufficient funding and focus, research that slows aging has the potential to do what no drug, surgical procedure, or behavior modification can do - add healthy years of life, and simultaneously postpone the costly and harmful conditions of old age.
"Age is the common denominator and number one risk factor to virtually every chronic disease we face. Scientists know that alterations in cell replacement and repair, stress response, and inflammation are the key influencers to the development of cancer, heart disease, diabetes, and other debilitating (and costly) conditions later in life. These are also the essential changes taking place in our aging bodies."
NO GENETIC LONGEVITY-CANCER BALANCE FOR HUMANS?
Work in laboratory animals has strongly suggested that cancer risk and longevity trade off against one another. A simplistic way of looking at it is this: if your stem cells are active enough to keep your tissues running well for longer, then they are also active enough to be at greater risk of producing a cancerous mutation. A recent twin study suggests that the genetics of the situation might not work that way for we humans:
"Animal models and a few human studies have suggested a complex interaction between cancer risk and longevity indicating a trade-off where low cancer risk is associated with accelerating aging phenotypes and, vice versa, that longevity potential comes with the cost of increased cancer risk. This hypothesis predicts that longevity in one twin is associated with increased cancer risk in the cotwin. ... A total of 4,354 twin pairs born 1900-1918 in Denmark were followed for mortality in the Danish Civil Registration System through 2008 and for cancer incidence in the period 1943-2008 through the Danish Cancer Registry. ... The 8,139 twins who provided risk time for cancer occurrence entered the study between ages 24 and 43 (mean 33 years), and each participant was followed up to death, emigration, or at least 90 years of age. The total follow-up time was 353,410 person-years and 2,524 cancers were diagnosed. ... This study did not find evidence of a cancer-longevity trade-off in humans. On the contrary, it suggested that longevity in one twin is associated with lower cancer incidence in the cotwin, indicating familial factors associated with both low cancer occurrence and longevity."
The highlights and headlines from the past week follow below. Remember - if you like this newsletter, the chances are that your friends will find it useful too. Forward it on, or post a copy to your favorite online communities. Encourage the people you know to pitch in and make a difference to the future of health and longevity!
LATEST HEADLINES FROM FIGHT AGING!
EFFICIENT TRANSDIFFERENTIATION OF SKIN CELLS TO NERVE CELLS
Friday, April 13, 2012
Transdifferentiation is showing up more often of late - the ability to switch somatic cells directly between types without having to go through an intermediate stage of reprogramming into stem cells. It should in theory make obtaining specific cells for research and therapy a cheaper and more reliable process in the future: "it has become possible to directly convert cells of the body into one another - without the time-consuming detour via a pluripotent intermediate stage. However, this method has so far been rather inefficient. [Scientists] have now developed the method to the point that it can be used for biomedical applications. ... [Researchers] are interested in the biomedical utilization of artificially produced human nerve cells for disease research, cell replacement, and the development of active substances. ... By blocking the so-called SMAD signaling pathway and inhibiting glycogen synthase kinase 3 beta (GSK3ß), they increased the transformational efficiency [of skin cells to neurons] by several times - and were thus able to even simplify the means of extraction. Using only two instead of previously three transcription factors and three active substances, [the] researchers were able to convert a majority [of] skin cells into neurons. In the end, their cell cultures contained up to more than 80% human neurons. ... We were able to demonstrate how the genes typical for skin fibroblast were gradually down-regulated and nerve-cell-specific genes were activated during the cell transformation. In addition, the nerve cells thus obtained were functionally active, which also makes them interesting as a source for cell replacement."
WHITE MATTER PATHWAYS AND COPING WITH THE UNFAMILIAR
Friday, April 13, 2012
As time progresses, researchers are increasingly able to correlate changing mental characteristics in aging with changing structure in the brain. Here is one example: "A brain-mapping study [has] found that people's ability to make decisions in novel situations decreases with age and is associated with a reduction in the integrity of two specific white-matter pathways that connect an area in the cerebral cortex called the medial prefrontal cortex with two other areas deeper in the brain. Grey matter is the part of the brain that contains the bodies of the neurons while white matter contains the cable-like axons that carry signals from one part of the brain to another. In the past, most brain-imaging research has concentrated on the grey matter. Recently, however, neuroscientists have begun looking more closely at white matter. It has been linked to the brain's processing speed and attention span, among other things, but this is the first study to link white matter to learning and decision making. ... The evidence that this decline in decision-making is associated with white-matter integrity suggests that there may be effective ways to intervene. Several studies have shown that white-matter connections can be strengthened by specific forms of cognitive training. ... The critical white-matter connections that the experiment identified run from the thalamus, a highly connected relay center in the brain, to the medial prefrontal cortex, an area of the brain involved with decision making, and from the medial prefrontal cortex to the ventral striatum, which is associated with the emotional and motivational aspects of behavior." You might also look at past research on age-related damage to white matter and its consequences on metal capacity.
ON THE STATE OF CANCER STEM CELL RESEARCH
Thursday, April 12, 2012
An article from the Scientist: "Based on new intelligence, oncologists are making informed battle plans to attack a particularly pernicious enemy - the cancer stem cell (CSC). Controversial though they are, cancer stem cells are an incredibly promising target. If treatment-resistant cancer, and the metastases that transplant the cancer throughout the body, could be attributed to the actions of a single cell type, it could explain many of the treatment failures and provide a novel way to attack the disease. The idea that cancers are driven by cells with 'embryonic features' is an old one. Many cancers regress to a less differentiated state, expressing proteins that are usually expressed only in the embryo or during early development. It is only in the past 20 years or so, however, that additional observations led to the hypothesis that these embryonic-like cells were a separate subpopulation that fueled tumor expansion, much the same way that stem cells churn out the cells that make up a particular organ. ... In the past 5 years there has been an exponential increase in CSC research. This research has helped to resolve a number of controversies regarding identification of these cells and their role in driving tumor growth and mediating treatment resistance. Despite these advances, the CSC field is still in its relative infancy, and many questions and challenges remain. More than a dozen biotechnology and pharmaceutical companies are now vigorously pursuing CSC research. As a result, a number of early-phase clinical trials targeting CSCs are in progress. These studies and the later-stage efficacy trials that follow them should indicate whether successful targeting of CSCs significantly improves outcomes in cancer patients. If this is found to be the case, it may usher in the beginning of a new era of cancer therapy."
Thursday, April 12, 2012
A look at why, in this age of biotechnology and great uncertainty over the degree to which life spans will be extended in the next few decades, it is unwise to trust your financial future to large pension and welfare institutions. Any significant progress over the present very modest baseline of incidental life extension through general advances in medicine will likely bring down much of the existing system in the years ahead - which of course suggests that big centralized pension systems should be avoided like the plague, but that won't happen. If today's politics are any guide, politicians will continue to aggressively devalue their national currencies, taking wealth from their broader population to pay for what cannot be afforded until such time as the house of cards cannot be propped up any longer. The lesson to be taken away here: expect to provide for your own financial security in later life, and act accordingly now: "Here's the issue: governments have done their analysis of the aging issue largely based on best guesses of population developments in the future. These developments include further drops in fertility and some further increase in longevity. The trouble is that in the past, longevity has been consistently and substantially underestimated. We all live much longer now than had been expected 30, 20, and even just 10 years ago. So there is a good chance in the future people will live longer than we expect now. We call this longevity risk - the risk we all live longer than anticipated. ... Why is that a risk, you may ask. We all like to live longer, healthy lives. Sure, but let's now return to those pension worries. If you retire at 65 and plan your retirement finances expecting to live another 20 years (assuming you have enough savings for at least that period), you would face a serious personal financial crisis if you actually live to 95, or - well in your 100s. You could rely on your social security system at that point, but the program is also counting on people not living much beyond their mid-80s in most countries. Your personal financial problem multiplies by the size of the population, and, for society as a whole, becomes a very large problem." An example of how the present politics and systems of wealth transfer reward irresponsibility at all levels until such time as growth in collective irresponsibility sinks the whole venture.
EXPLAINING HOW ALTERED IGF-1 SIGNALING EXTENDS LIFE
Wednesday, April 11, 2012
Signs of progress in understanding the mechanisms of induced longevity through altered insulin/IGF-1 signaling are shown in this paper. This is one of the most-studied class of longevity mutations in lower animals, despite there being some debate over whether it is relevant to mammal biochemistry. Here, the basic mechanism is explained as being hormetic, centering on the mitochondria: researchers "elucidate a conserved mechanism through which reduced insulin-IGF1 signaling activates an AMP-kinase-driven metabolic shift toward oxidative proline metabolism. This, in turn, produces an adaptive mitochondrial [reactive oxygen species (ROS)] signal that extends worm life span. These findings further bolster the concept of mitohormesis as a critical component of conserved aging and longevity pathways. ... Impaired insulin and IGF-1 signaling (iIIS) in C. elegans daf-2 mutants extends life span more than 2-fold. Constitutively, iIIS increases mitochondrial activity and reduces reactive oxygen species (ROS) levels. By contrast, acute impairment of daf-2 in adult C. elegans reduces glucose uptake and transiently increases ROS. Consistent with the concept of mitohormesis, this ROS signal causes an adaptive response by inducing ROS defense enzymes, culminating in ultimately reduced ROS levels despite increased mitochondrial activity. Inhibition of this ROS signal by antioxidants reduces iIIS-mediated longevity by up to 60%. ... IIIS upregulates mitochondrial L-proline catabolism, and impairment of the latter impairs the life span-extending capacity of iIIS while L-proline supplementation extends C. elegans life span. Taken together, iIIS promotes L-proline metabolism to generate a ROS signal for the adaptive induction of endogenous stress defense to extend life span."
AN UPDATE ON COMPARATIVE STUDIES OF LONGEVITY
Wednesday, April 11, 2012
Researchers are comparing the biochemistry of long-lived species to better understand the roots of large differences in life span: "The team looked at the genome of more than 30 mammalian species to identify proteins that evolve in connection with the longevity of a species. They found that a protein, important in responding to DNA damage, evolves and mutates in a non-random way in species that are longer-lived, suggesting that it is changing for a specific purpose. They found a similar pattern in proteins associated with metabolism, cholesterol and pathways involved in the recycling of proteins. Findings show that if certain proteins are being selected by evolution to change in long-lived mammals like humans and elephants, then it is possible that these species have optimized pathways that repair molecular damage, compared to shorter-lived animals, such as mice. ... The genetic basis for longevity differences between species remains a major puzzle of biology. A mouse lives less than five years and yet humans can live to over 100 for example. If we can identify the proteins that allow some species to live longer than others we could use this knowledge to improve human health and slow the aging process."
EVIDENCE FOR CALORIE RESTRICTION TO IMPROVE HEART CELL BEHAVIOR
Tuesday, April 10, 2012
This is work performed on cells rather than organisms, but it still might be added to the great weight of existing evidence to suggest that calorie restriction improves most aspects of health: "Heart cells starved of nutrients are less likely to be damaged during periods of decreased blood flow and sudden influxes of blood, known as ischemia and reperfusion, and are also less likely to get out of synch with their cellular neighbors, the damaging phenomenon called arrhythmia. ... scientists learned that starved heart cells maintain normal calcium cycling and basic mitochondrial function far longer than non-starved cells during periods of extreme stress. The findings [add] to a growing body of scientific evidence that suggests the consumption of less energy - while maintaining balanced nutrition - can benefit tissues by enhancing cell performance and reducing DNA damage associated with the aging process. ... We are connecting several loose facts about calorie restriction and heart function, in particular, arrhythmias. We have shown why nutrient restriction protects the cells from ischemia and reperfusion. Normal function means less risk of arrhythmias, during which heart cells stop communicating properly with each other, and which can cause further damage, even sudden cardiac death. ... The scientists studied cultured heart cells originally derived from young rats. The cells were grown in a 2 cm-by-2 cm monolayer, to allow ease of study. The researchers mapped intracellular calcium ions and mitochondrial membrane potential with the help of fluorescent tags. Ischemia was simulated by placing a 1.8 cm-by-1.8 cm cover slip over the center of the cell culture, which limited oxygen and nutrient flow to that portion of the culture. Reperfusion was simulated by the removal of the cover slip. ... These experiments are not yet telling us whether we can emulate the effects of nutrient restriction in humans to lessen the damage of ischemia-reperfusion. But we have shown one way nutrient restriction may be acting to reduce heart tissue damage, a subject of interest to many laboratories."
IMMUNE SYSTEM AGING IN A NUTSHELL
Tuesday, April 10, 2012
A review paper: "With the improvement of medical care and hygienic conditions, there has been a tremendous increment in human lifespan. However, many of the elderly (older than 65 years) display chronic illnesses, and a majority requires frequent and longer hospitalization. The robustness of the immune system to eliminate or control infections is often eroded with advancing age. Nevertheless, some elderly individuals do cope better than others. The origin of these inter-individual differences may come from genetic, lifestyle conditions (nutrition, socio-economic parameters), as well as the type, number and recurrence of pathogens encountered during life. The theory we are supporting is that chronic infections, through life, will induce profound changes in the immune system probably due to unbalanced inflammatory profiles. Persistent viruses such as cytomegalovirus are not eliminated and are a driven force to immune exhaustion. Because of their age, elderly individuals may have seen more of these chronic stimulators and have experienced more reactivation episodes ultimately leading to shrinkage of their repertoire and overall immune robustness." Evidence in recent years suggests that this issue can be addressed by selectively destroying immune cells devoted to largely useless causes such cytomegalovirus - a goal that becomes ever more practical as targeted cell-killing therapies move closer to the clinic.
INVESTIGATING AGELESSNESS IN SEA URCHINS
Monday, April 9, 2012
Some species of sea urchin, you may recall, age so slowly that it is hard to talk about life expectancy or pin down the likely age of a particular specimen with any ease. As for lobsters, another near-ageless collection of species, there isn't actually all that much research taking place into the biology of aging and longevity in these animals. Here is an example, however: "The life history of sea urchins is fundamentally different from that of traditional models of aging and therefore they provide the opportunity to gain new insight into this complex process. Sea urchins grow indeterminately, reproduce throughout their life span and some species exhibit negligible senescence. Using a microarray and qRT-PCR, age-related changes in gene expression were examined in three tissues (muscle, esophagus and nerve) of the sea urchin species Strongylocentrotus purpuratus. The results indicate age-related changes in gene expression involving many key cellular functions such as the ubiquitin-proteasome pathway, DNA metabolism, signaling pathways and apoptosis. Although there are tissue-specific differences in the gene expression profiles, there are some characteristics that are shared between tissues providing insight into potential mechanisms that promote lack of senescence in these animals. As an example, there is an increase in expression of genes encoding components of the Notch signaling pathway with age in all three tissues and a decrease in expression of the Wnt1 gene in both muscle and nerve. The interplay between the Notch and Wnt pathways may be one mechanism that ensures continued regeneration of tissues with advancing age contributing to the general lack of age-related decline in these animals."