The scientific consensus these days is that ingesting antioxidants in the hope of improving your metabolism isn't going to work.

Since the early 1990s scientists have been putting these compounds through their paces, using double-blind randomised controlled trials - the gold standard for medical intervention studies. Time and again, however, the supplements failed to pass the test. True, they knock the wind out of free radicals in a test tube. But once inside the human body, they seem strangely powerless. Not only are they bad at preventing oxidative damage, they can even make things worse. Many scientists are now concluding that, at best, they are a waste of time and money. At worst they could be harmful.

It is, however, quite true that the antioxidants generated by your own biochemistry are important in health and longevity. Some of the difference in longevity between species is ascribed to the degree to which they manufacture their own antioxidants:

It's reasonable to theorize that if you happen to be a member of a species that naturally generates a lot of antioxidants around the mitochondria, you're going to live longer than members of another, similar species with worse luck in the antioxidant stakes.

The key here appears to be where the antioxidants end up performing their work. Mouse studies have shown that carefully directing antioxidants to the cellular mitochondria extends healthy life span on the order of 20-30% - a fairly complex feat of biochemical engineering that no presently available pill can match. Those studies further showed that no benefit emerges from the same antioxidants sent elsewhere in mouse biochemistry. If you'd like to learn more about why antioxidants in the mitochondria make such a large different, head back into the archives for an outline of the Mitochondrial Free Radical Theory of Aging: mitochondria create free radicals that cause all sorts of damage, but targeted antioxidants can soak up some portion of the free radicals before that damage occurs.

Our biology is complex - why would we expect that successfully modifying it with chemicals would be as simple as eating those chemicals? Ingesting antioxidants in the hope of benefit because they happen to do certain things in certain portions of your biochemistry is magical thinking given the evidence on the table to date. It certainly doesn't have the best record in experimental studies. Here's one of the latest:

New study on antioxidants shows mixed results for life extension:

First the good news: a study by scientists at the Buck Institute for Age Research shows four common antioxidants extended lifespan in the nematode worm C. elegans. And the not such good news: those four were among 40 antioxidants tested, the majority of which did nothing or caused harm to the microscopic worms.

...

“We’ve taken a careful look at the way antioxidants affect aging in simple animals and what we find is that it’s a hodge-podge of effects,” said Buck Faculty member Gordon Lithgow, PhD, lead author of the study. “We see antioxidants that appear to make simple invertebrates live healthier, longer lives and we also find antioxidants that have precisely the opposite effect, that compromise the animal’s survival,” he said.

...

"I’m an optimist, I think we can make positive statements about the potential for intervening in aging with compounds that manage oxidative stress,” said Lithgow. “I’m also saying that we’re not there yet, and if only four of the 40 compounds are having the desired effect, that’s not good when we think about applying these results to humans today.”

Posted by Reason at 8:04 PM
Permanent Link | View Comments (2) | Post Comment | TrackBack (0)

Our immune systems slowly become ineffective with age, a consequence of their evolved design and exposure to persistent viruses like CMV across a lifetime.

Your immune system is capped in its use of resources; it can only have a set number of T cells in operation at one time. A reserve of naive T cells is needed to effectively respond to new threats. These are untrained cells that will be educated and drafted to combat new intrusions. A small reserve of memory cells is needed to respond effectively to previously encountered threats - one reserve per threat. The more threats you have encountered, the more cells become devoted to memory; eventually you don't have enough naive T cells left to mount any sort of effective defense.

This contributes to a range of problems, starting with a lack of resistance to disease, one of the roots of age-related frailty, and most likely including buildup of damage-inducing senescent cells and increased risk of cancer with age. The immune system is responsible for destroying errant cells of all sorts, and so it is reasonable to speculate on the degree to which cancer risks can be blamed on immune system dysfunction:

Compromised immunity contributes to the decreased ability of the elderly to control infectious disease and to their generally poor response to vaccination. It is controversial as to how far this phenomenon contributes to the well-known age-associated increase in the occurrence of many cancers in the elderly. However, should the immune system be important in controlling cancer, for which there is a great deal of evidence, it is logical to propose that dysfunctional immunity in the elderly would contribute to compromised immunosurveillance and increased cancer occurrence.

The chronological age at which immunosenescence becomes clinically important is known to be influenced by many factors, including the pathogen load to which individuals are exposed throughout life. It is proposed here that the cancer antigen load may have a similar effect on "immune exhaustion" and that pathogen load and tumor load may act additively to accelerate immunosenescence. Understanding how and why immune responsiveness changes in humans as they age is essential for developing strategies to prevent or restore dysregulated immunity and assure healthy longevity, clearly possible only if cancer is avoided.

Here, we provide an overview of the impact of age on human immune competence, emphasizing T-cell-dependent adaptive immunity, which is the most sensitive to ageing. This knowledge will pave the way for rational interventions to maintain or restore appropriate immune function not only in the elderly but also in the cancer patient.

That's an open access paper, so don't miss the PDF link underneath the abstract. It is pleasing to see researchers outside the normal pro-longevity groups thinking in terms of restoring youthful function - that's very necessary to the future of medicine I'd like to see.

Posted by Reason at 7:43 PM
Permanent Link | View Comments (1) | Post Comment | TrackBack (0)

Here is an example of what I think is a passable submission to Google's Project 10¹⁰⁰, with a focus on mitochondrial science. I could probably run one up for LysoSENS-like work as well, but one thing at a time.

Your idea's name (50 characters maximum):

Bring Mitochondrial Repair to Phase 1 Trials

What one sentence best describes your idea? (maximum 150 characters):

Our mitochondria degrade over the years, contributing greatly to age-related disease and frailty - but medical technology can fix this problem.

Describe your idea in more depth. (maximum 300 words):

I propose that the most promising of nascent mitochondrial repair technologies be funded from their present early-stage standing to readiness for Phase I clinical trials in humans. As a condition of funding, methodologies will be published free of restriction for any group to further develop and bring to market. This will be accomplished with the aid of a non-profit research organization like the Methuselah Foundation, with a history of raising matching funds for large donations, so as to maximize the impact of the funding program.

Mitochondria are tiny power plants inside our cells, churning away to turn food into energy. They were once free-roaming bacteria and have retained their own mitochondrial DNA, distinct from our own nuclear DNA. As our mitochondria fail, however, so do we. The Mitochondrial Free Radical Theory of Aging points to progressive damage to our mitochondrial DNA as an important - and arguably the most important - root cause of age-related degeneration, disease, and frailty.

At present, a range of plausible technologies exist to repair mitochondrial DNA, replace mitochondrial DNA, or make damage to this DNA irrelevant. These technologies stand at varying points between ideation and animal trials: whole-body replacement of mitochondrial DNA was demonstrated in mice as early as 2005, for example, as has the process of allotopic expression: moving a single important mitochondrial gene into the cellular nucleus, such that the necessary proteins are still made, and a damaged mitochondrion continues to function.

These technologies are progressing very slowly and with a paucity of funding, partly because this is the nature of early research, partly because of perverse regulatory incentives. This is unacceptable when considered against a) the comparatively low cost of basic research in this age of biotechnology, and b) the vast potential benefits to humanity. Philanthropic funding can overcome these hurdles.

What problem or issue does your idea address? (maximum 150 words):

Consequences of damaged mitochondrial DNA include failing organs, clogged arteries, neurodegeneration, and much more. This is the Mitochondrial Free Radical Theory of Aging, well supported by decades of evidence. A working repair technology pushed into the clinical system has the potential to entirely remove this large contribution to disease and frailty. But first it must be finalized from the promising beginnings presently in the laboratory.

Regulatory bodies like the FDA restrict all application of medical science to specific, named diseases; this makes early stage research to produce a general repair technology for mitochondria unprofitable. It would be hard to license, as a developer would struggle to make money on that license. Yet it costs little to move established research to Phase I trial readiness - $1 million is a fortune for a single laboratory - and developers leap at license-free medical technology. This is where careful philanthropy can unjam the gridlocked system.

If your idea were to become a reality, who would benefit the most and how? (maximum 150 words):

A mitochondrial repair technology demonstrated to be ready for human trials, free of licensing cost, free from intellectual property restrictions, and unjammed from the system of perverse incentives in early-stage research stands to benefit everyone. It will be as universally beneficial a medicine as aspirin; the elderly will benefit immediately upon availability, we will benefit from it in decades to come, and our children will benefit when their bodies too start to run down.

Everyone has mitochondria, and mitochondrial degeneration is a universal condition, bringing myriad forms of suffering and pain. We got rid of tuberculosis and smallpox as soon as we could, so why not this? Repair of mitochondrial DNA damage is a very plausible near-future win for everyone, given where the science is today. We can make it happen.

What are the initial steps required to get this idea off the ground? (maximum 150 words):

I envisage the opening labor as follows: 1) Identify the existing non-profit research group and volunteer cadre to run this project - my vote is for the Methuselah Foundation, given their record and contacts within the research community, and the way their mission aligns with that of this project; 2) Identify the best groups and laboratories presently engaged in mitochondrial repair and related research; 3) Develop prospective work, milestone, and funding plans with researchers; 4) Start raising matching funds through existing channels; 5) Select the initial funding opportunities from the best of those produced, and get the researchers to work.

From there, I would like to see established a low-overhead but effective volunteer group of researchers and advocates to manage the cycle of grants, matching fundraising, and evaluation of progress and new research opportunities going forward.

Describe the optimal outcome should your idea be selected and successfully implemented. How would you measure it? (maximum 150 words):

The optimal outcome, after the completion of the project, is: a) for one or more different repair technologies to be successfully readied for Phase 1 human trials; b) protocols and methods to be fully detailed and published, free of restriction; c) multiple medical development concerns to be working on bringing applications to market in diverse regulatory regions; d) independently funded follow-on research taking place with the aim of improving upon the initial technology; e) matching fundraising to effectively continue even after the Google grant is complete.

Sample metrics for success include: a) the breadth and effectiveness of the technologies developed; b) the quality of the published material; c) range of developers working on applications; d) the range of independently funded lines of work spawned by this philanthropic funding; and, most crucially, e) the amount of matching funding and independent research and development funding drawn by this philanthropic project.

If you'd like to recommend a specific organization, or the ideal type of organization, to execute your plan, please do so here. (maximum 50 words):

The ideal organization is a research non-profit with existing connections to scientists already involved in mitochondrial repair research, a very low cost of operation for delivered funding, and a history of raising matching funds for large donations. The ideal example is the Methuselah Foundation, as you might have gathered.

Posted by Reason at 6:08 PM
Permanent Link | View Comments (4) | Post Comment | TrackBack (0)

Google is running an initiative called Project 10¹⁰⁰, similar to the Amex Members Project that the Methuselah Foundation volunteers and healthy life extension community recently took a swing at winning. People are invited to submit ideas for charitable projects that will benefit humanity; Google employees winnow down the (no doubt thousands of) entries to the 100 they like the most; the public at large vote on the 100; and an advisory board picks five to split $10 million in funding. From the FAQ:

Q: How will you decide which ideas to fund?
A: A selection of Google employees will review all the ideas submitted and select 100 for public consideration. The 100 top ideas will be announced on January 27, 2009, at which point we will invite the public to select twenty semi-finalists. An advisory board will then choose up to five final ideas for funding and implementation. We plan to announce these winners in early February.

Q: Who is on the advisory board?
A: The advisory board will be composed of five to seven individuals known for their expertise in the submission categories.

Q: What criteria will be used to select the winning ideas?
A: The following five criteria will be considered by the advisory panel in evaluating and selecting the winning ideas:

Reach: How many people would this idea affect?
Depth: How deeply are people impacted? How urgent is the need?
Attainability: Can this idea be implemented within a year or two?
Efficiency: How simple and cost-effective is your idea?
Longevity: How long will the idea's impact last?

...

Q. How will Google implement these ideas?
Once we've selected up to five ideas for funding, we will begin an RFP process to identify the organization(s) and proposals that are in the best position to help implement the selected ideas.

Q: I know an organization that I believe can implement my idea if it is selected. What should I do?
The submission form includes a field where you can recommend an organization to implement your idea. If your idea is selected for funding, we will contact this organization when we begin the selection process for the implementation phase. Please note that this does not guarantee that they will be chosen to implement the idea.

As for the Amex Members Project there is a disconnect between voting and the advisory board choice: there is no guarantee that strong support for a longevity science proposal that made it into the top 100 would see it funded. But it costs little for us to try - if you don't swing at the balls that come out of the blue, you certainly won't hit any of them into the outfield.

The submission deadline for ideas is October 20th. I encourage you all to think carefully about a good longevity science project to submit for consideration to Project 10¹⁰⁰:

• Is the project scope appropriate for a $1-2 million award?
• Are you referencing the organizations you think best able to carry it out - such as the Methuselah Foundation?
• Carefully consider Google's requirements - especially the time requirement for implementation, given the way in which medical research works.

Other than that - have at it! This is a competition of merit in the early stages: if you think your plan has merit, then submit it. It doesn't matter if someone else has submitted a similar plan, and in fact I suspect that volume of similar (not the same, but similar) project submissions is a metric all of its own by which Google staff will judge merits. The more varied project submissions there are relating to engineered longevity, the more likely it is that Google employees sympathetic to the cause will see them and move one or more of them ahead into the top 100.

Posted by Reason at 11:32 AM
Permanent Link | View Comments (1) | Post Comment | TrackBack (0)

Chris Patil of Ouroboros is blogging this year's Cold Spring Harbor Labs conference on the molecular genetics of aging. You might recall his coverage of the 2006 meeting as well. This time round:

I’m going to try to blog the sessions a bit more than I did last time, though I’m not sure how that will work out. Actually taking notes at the same time as I make blog entries sounds pretty hard. Still, though, I’ll try.

The first conference post is up:

This first session focused on the smaller model organisms that led the first wave of modern biogerontology: yeast, worm, and fly. The talks covered a wide range of systems and techniques, but they held together nicely because they (mostly) converged on common themes: control of calorie-restriction-mediated lifespan extension, and the genetics of the insulin-like growth factor pathway that governs lifespan in many organisms.

A lot of interesting detail follows, so take a look.

UPDATE: The rest of the session posts:

• CSHL 2008, Session II: Genome stability, damage & repair
• CSHL 2008, Session II: Telomeres
• CSHL 2008, Session VI: Senescence, apoptosis and stress
• CSHL 2008, Session VII: Stem cells
• CSHL 2008, Session X: Environmental interventions

Stephen Spindler (current Mprize record holder for mouse rejuvenation) started off with the refreshing title "Searching for longevity therapeutics." He discussed a variety of strategies to identifying lifespan extension drugs, as well as some of their shortcomings, and then proceeded to describe aging-intervention studies currently ongoing in his lab. The project is testing a variety of CR mimetics as well as orally bioavailable rapamycin, green tea flavonoids (which inhibit fatty acid synthase), a histone deacetylase inhibitor, and microencapsulated curcumin. Also on the list are statins, AGE breakers, omega 3 fatty acids, and old standbys of the life-extension movement like DHA, Juvenon (cartinine/lipoate), and resveratrol. No results yet, but we’ll be eagerly awaiting the outcome of these studies.

Posted by Reason at 7:33 PM
Permanent Link | View Comments (0) | Post Comment | TrackBack (0)

Today I thought I'd share a readable overview of presently discovered longevity genes: how they fit into a small number of broad categories, and are surprisingly similar across a range of different organisms. It's an open access paper, so don't miss the PDF link underneath the abstract.

Longevity Genes: Insights from Calorie Restriction and Genetic Longevity Models

In this review, we discuss the genes and the related signal pathways that regulate aging and longevity by reviewing recent findings of genetic longevity models in rodents in reference to findings with lower organisms. We also paid special attention to the genes and signals mediating the effects of calorie restriction, a powerful intervention that slows the aging process and extends the lifespan in a range of organisms.

An evolutionary view emphasizes the roles of nutrient-sensing and neuroendocrine adaptation to food shortage as the mechanisms underlying the effects of CR. Genetic and non-genetic interventions without CR suggest a role for single or combined hormonal signals that partly mediate the effect of CR.

Longevity genes fall into two categories, genes relevant to nutrient-sensing systems and those associated with mitochondrial function or Redox regulation. In mammals, disrupted or reduced growth hormone (GH)-insulin-like growth factor (IGF)-1 signaling robustly favors longevity. CR also suppresses the GH-IGF-1 axis, indicating the importance of this signal pathway.

Surprisingly, there are very few longevity models to evaluate the enhanced anti-oxidative mechanism, while there is substantial evidence supporting the oxidative stress and damage theory of aging. Either increased or reduced mitochondrial function may extend the lifespan. The role of Redox regulation and mitochondrial function in CR remains to be elucidated.

It is my impression from watching this all develop for some few years that mitochondrial research is where the big payoff is in the mainstream of aging research - those researchers who are not yet thinking along the lines of damage repair strategies, but are instead moving ahead with a slower approach. Half the field is working on a range of interconnected metabolic control mechanisms, which I can't see producing anywhere near as dramatic results as quickly as a full-court press towards repairing mitochondrial damage. Even somewhat slowing oxidative damage to mitochondria produces gains in life span in mice that are on the same order as that of calorie restriction - imagine what we could do with one of the more comprehensive mitochondrial repair technologies presently under development.

Posted by Reason at 7:14 PM
Permanent Link | View Comments (0) | Post Comment | TrackBack (0)

Researcher João Pedro de Magalhães - author of the excellent senescence.info website - is now set up with his own lab at Liverpool University across the pond. He'll be forming up the The Integrative Genomics of Aging Group and getting to work on what is clearly his passion. From the research introduction:

Ageing has a profound impact on human society and modern medicine, yet it remains a major puzzle of biology. Our group aims to help understand the genetic, cellular, and molecular mechanisms of ageing. Although our research integrates different strategies, its focal point is developing and applying computational and experimental methods that help bridge the gap between genotype and phenotype, a major challenge of the post-genome era, and help decipher the human genome and how it regulates complex processes like ageing.

In the long term, we would like our work to help ameliorate age-related diseases and preserve health. No other biomedical field has so much potential to improve human health as research on the basic mechanisms of ageing.

...

Because longevity evolved in the human lineage, we are particularly interested in employing modern computational methods in primates to study the evolution, structure, and function of genes associated with ageing, which may shed light on the genetic changes that contributed to the evolution of human longevity. Ultimately, our goal is to understand why we are different from each other and from other species and what is the role of each DNA base in the genome in determining these differences, in particular in the context of ageing and age-related diseases.

This is all fresh from the presses, and there are possibilities for undergraduates and postgraduates to help with this work. Take a look if you're at that stage in a life science career, and haven't already been spirited away by the Methuselah Foundation's Undergraduate Research Initiative.

For my part, I'm pleased to see that the goal of intervening in aging is ceasing to be the dreaded third rail of grantsmanship that must not be mentioned. As more labs around the world are founded with the explicitly stated agenda of treating aging to improve the human condition, the tide of public support and understanding will continue to turn. It's that tide, the broad sentiment of support for longevity science, that will sustain much needed growth in the research community over the long haul.

Posted by Reason at 7:39 PM
Permanent Link | View Comments (0) | Post Comment | TrackBack (0)

Words of wisdom from the scientific community:

On March 19, 2008 a Symposium on Pathophysiology of Ageing and Age-Related diseases was held in Palermo, Italy. Here, the lecture of V. Nicita-Mauro on Smoking, health and ageing is summarized. Smoking represents an important ageing accelerator, both directly by triggering inflammatory responses, and indirectly by favouring the occurrence of several diseases where smoking is a recognized risk factor. Hence, non-smokers can delay the appearance of diseases and of ageing process, so attaining longevity.

Forms of slow self-destruction are many and varied amongst we humans: smoking, not practicing calorie restriction, failing to keep up a good relationship with a physician, piling on the visceral fat, failing to exercise, and so forth. The vast majority of people are quite comfortable engaging in habits that cause great harm to the old person they will one day be - cutting off years or even decades of health.

This is all a good example of time preference at work: we are hardwired to deeply discount the value of the future, even when it's our own future. What we don't value, we squander - you can see that maxim in action everywhere.

Many of the strategies for success in life revolve around doing what needs to be done rather than what you'd like to be doing - ignoring the inner time preference voice in favor of working towards long-term goals. Saving for retirement, for example. In just the same way, living in good health for long enough to benefit from a future of longevity therapies requires us to act as though future years of health are valuable. They are in fact very valuable: if you lose them, you also lose the chance at decades or even centuries more healthy life made possible by future advances in medical science.

Posted by Reason at 7:17 PM
Permanent Link | View Comments (1) | Post Comment | TrackBack (0)

Regular readers should by now know that accumulating damage to the mitochondria, the power plants of your cells, contributes to degenerative aging. That damage is a side-effect of being alive - it's something like corrosion in power plant internals, an by-product of operation. When I've talked about this in the past, it's usually in the context of the chain of consequences that occurs when free radicals (or reactive oxygen species) produced by the mitochondria damage mitochondrial DNA. Damage to the mitochondrial DNA eventually means that important proteins, part of the mitochondrial power-generating machinery, are no longer produced. It goes downhill from there.

Regular readers should also recall the evidence for glycation as a bad thing for your long term health. Sugars have a way of running rampant through your biochemistry, gumming together important molecules for a while in glycation reactions, and creating new biochemicals called advanced glycation endproducts (AGEs). The AGEs then trigger abnormal behavior in your cells via the receptor for AGE, or RAGE. The more gylcation that takes place, the more damage your metabolism suffers - and aging is all about rising levels of damage.

Last year, I mentioned a demonstration of life extension in nematode worms achieved by reducing the level of glycation. Researchers increased the levels of a natural enzyme called glyoxalase that reduces the levels of glycated chemicals: this is somewhat analogous to using antioxidants to reduce oxidative stress and levels of free radicals. Today, I noticed the following paper, which theorizes that glycation also causes damage to mitochondria, possibly by preventing vital mitochondrial proteins from doing their jobs, and that lower levels of glycation also reduce the problems that are characteristic of mitochondrial damage.

Dicarbonyls linked to damage in the powerhouse: glycation of mitochondrial proteins and oxidative stress

Protection of mitochondrial proteins from glycation by endogenous dicarbonyl compounds, methylglyoxal and glyoxal, was found recently to prevent increased formation of reactive oxygen species and oxidative and nitrosative damage to the proteome during aging and produce life extension in the nematode Caenorhabditis elegans.

This suggests that dicarbonyl glycation damage to the mitochondrial proteome may be a preceding event to mitochondrial dysfunction leading to oxidative stress. Future research will address the functional changes in mitochondrial proteins that are the targets for dicarbonyl glycation.

More direct evidence is needed to bolster this theory offered to explain the observed results - but isn't it interesting to see how everything links back to the mitochondria in one way or another?

Posted by Reason at 7:13 PM
Permanent Link | View Comments (0) | Post Comment | TrackBack (0)

Lipofuscin is the name given to a gunk formed of many varied chemical byproducts of metabolism. It accumulates in your cells with age - and cause a great many problems in doing so. In particular, it accumulates in lysosomes, the recycling units of your cells that are tasked with breaking down unwanted chemical and components (the latter in the process called autophagy). Lysosomes in the old are bloated and inefficient, packed to the gills with lipofuscin that cannot be broken down by the enzymes available to your cells. If your lysosomes aren't working well, then the process of autophagy isn't working well, and you can look back into the Fight Aging! archives to see why that is an issue:

You might think of autophagy as a form of self-maintenance for your cells: it is the destruction of damaged and older cellular components such that newly built components can take their place. It is an attractive, intuitive idea that an increased level of autophagy leads to consistantly better function in cells, which in turn leads to longer-lived animals.

I noticed some coverage today on research into the mechanisms by which lipofuscin is formed, which turns out to tie into iron build up and neurodegeneration:

A glitch in the ability to move iron around in cells may underlie a disease known as Type IV mucolipidosis ( ML4 ) and the suite of symptoms - mental retardation, poor vision and diminished motor abilities - that accompany it ... The same deficit also may be involved in aging and neurodegenerative diseases such as Alzheimer's and Parkinson's

...

To explore the possible role of iron transport in the disease, Xu's group focused on a protein called TRPML1 [that is responsible for ferrying iron out of the lysosome]. A mutation in the gene that produces TRPML1 is known to cause ML4

...

Further experiments confirmed that when TRPML1 is defective, iron becomes trapped in the lysosome. One result of the buildup is formation of a brownish waste material, lipofuscin, known as the "aging pigment." In skin cells, lipofuscin is the culprit responsible for the dreaded liver spots that appear with increasing age, but in nerve, muscle and other cells, its accumulation has more serious consequences.

"How lipofuscin causes problems in neurons and muscles is not clear, but it's believed that this is garbage that, in time, compromises the normal function of the lysosome," Xu said. "And we know the lysosome is important for all kinds of cell biology, particularly the recycling of intracellular components, so if it's damaged, the cell is going to suffer." Indeed, abnormal accumulation of lipofuscin is associated with a range of disorders including Alzheimer's disease, Parkinson's disease, and macular degeneration (a degenerative disease of the eye) and also contributes to the aging process.

"In a sense we can think of ML4 as really early onset of aging," Xu said.

...

"If we can somehow manipulate the lysosome iron level, we probably can provide a treatment for the patient," Xu said. "We're not far enough along for those kinds of experiments yet, but now we know enough to work toward that goal."

This is an interesting avenue of research, but it isn't clear whether it could lead to a way to reverse the problem or merely slow it down. Compare that with the bioremediation approach started by Methuselah Foundation-funded researchers. In that line of work, the aim is isolate bacterial enzymes that break down lipofuscin and that can be safely introduced into the body. Using such enzymes would remove the lipofuscin and thereafter keep it at very low levels, too low to cause issues or contribute to age-related disease.

Posted by Reason at 8:10 PM
Permanent Link | View Comments (0) | Post Comment | TrackBack (0)

Here is the outline of an interesting experiment:

• take a group of ordinary people and start them on the practice of calorie restriction (CR)
• extract serum from the participants' blood plasma before starting and after some months of CR
• culture cells on both sets of serum and examine the differences in biochemistry

You'll find that the CALERIE study research teams have done just this. The abstract is at PubMed:

Calorie restriction (CR) produces several health benefits and increases lifespan in many species. Studies suggest that alternate-day fasting (ADF) and exercise can also provide these benefits. Whether CR results in lifespan extension in humans is not known and a direct investigation is not feasible. However, phenotypes observed in CR animals when compared to ad libitum fed (AL) animals, including increased stress resistance and changes in protein expression, can be simulated in cells cultured with media supplemented with blood serum from CR and AL animals.

Two pilot studies were undertaken to examine the effects of ADF and CR on indicators of health and longevity in humans. In this study, we used sera collected from those studies to culture human hepatoma cells and assessed the effects on growth, stress resistance and gene expression. Cells cultured in serum collected at the end of the dieting period were compared to cells cultured in serum collected at baseline (before the dieting period).

Cells cultured in serum from ADF participants showed a 20% increase in Sirt1 protein which correlated with reduced triglyceride levels. ADF serum also induced a 9% decrease in proliferation and a 25% increase in heat resistance. Cells cultured in serum from CR participants induced an increase in Sirt1 protein levels by 17% and a 30% increase in PGC-1alpha mRNA levels.

This first in vitro study utilizing human serum to examine effects on markers of health and longevity in cultured cells resulted in increased stress resistance and an up-regulation of genes proposed to be indicators of increased longevity.

As of late 2008, I'd guesstimate that something in the order of one to two billion dollars have been invested into developing drugs that will produce some fraction of the effects of calorie restriction on mammalian biochemistry - such as increasing the expression of Sirt1. Most people can get these benefits for free, however, by simply eating a less calorie-packed diet. You should look into it - calorie restriction isn't anywhere near as hard as those who have never tried it make it out to be.

Posted by Reason at 7:44 PM
Permanent Link | View Comments (2) | Post Comment | TrackBack (0)

I notice that it has been quite some time since I last updated the Fight Aging! advertising policy. The old policy - with its focus on gathering donations in the early days of the Methuselah Foundation - certainly doesn't reflect the present state of affairs. It's been some months since I dropped all for-pay advertising for my websites, and that makes the new policy short and to the point. Here it is:

Fight Aging! does not sell advertising space. Banners and advertisements that appear on this website are there because I think the cause is good. I typically draw attention to nonprofits that fund aging science, specific research initiatives aimed at enhancing longevity, longevity research journals, and patient advocacy groups working to speed research into the repair of aging.

How much easier some things become in the absence of money changing hands.

Posted by Reason at 7:24 PM
Permanent Link | View Comments (1) | Post Comment | TrackBack (0)