Progress on Two Important SENS Anti-Ageing Themes

Aging Damage	Discovery	SENS Solution
Cell loss, tissue atrophy	19551	Stem cells and tissue engineering (RepleniSENS)
Nuclear [epi]mutations (only cancer matters)	19592, 19823	Removal of telomere-lengthening machinery (OncoSENS)
Mutant mitochondria	19724	Allotopic expression of 13 proteins (MitoSENS)
Death-resistant cells	19655	Targeted ablation (ApoptoSENS)
Tissue stiffening	19586, 19817	AGE-breaking molecules (GlycoSENS); tissue engineering
Extracellular aggregates	19078	Immunotherapeutic clearance (AmyloSENS)
Intracellular aggregates	19599	Novel lysosomal hydrolases (LysoSENS)

The "seven pillars of SENS anti-aging strategies" are shown in the table above, with a timeline of the discovery of their importance shown in the image below.

Important progress has recently been made on two of the pillars of SENS: Correcting for mutant mitochondria, and an improved clearing of cellular junk.

First, correcting human mitochondrial mutations:

Researchers at the UCLA stem cell center and the departments of chemistry and biochemistry and pathology and laboratory medicine have identified, for the first time, a generic way to correct mutations in human mitochondrial DNA by targeting corrective RNAs, a finding with implications for treating a host of mitochondrial diseases. Mutations in the human mitochondrial genome are implicated in neuromuscular diseases, metabolic defects and aging. There currently are no methods to successfully repair or compensate for these mutations, said study co-senior author Dr. Michael Teitell, a professor of pathology and laboratory medicine and a researcher with the Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research at UCLA.

Between 1,000 and 4,000 children per year in the United States are born with a mitochondrial disease and up to one in 4,000 children in the U.S. will develop a mitochondrial disease by the age of 10, according to Mito Action, a nonprofit organization supporting research into mitochondrial diseases. In adults, many diseases of aging have been associated with defects of mitochondrial function, including diabetes, Parkinson's disease, heart disease, stroke, Alzheimer's disease and cancer.

"I think this is a finding that could change the field," Teitell said. "We've been looking to do this for a long time and we had a very reasoned approach, but some key steps were missing. Now we have developed this method and the next step is to show that what we can do in human cell lines with mutant mitochondria can translate into animal models and, ultimately, into humans."

The study appears March 12, 2012 in the peer-reviewed journal Proceedings of the National Academy of Sciences. _esciencenews

More at the link.

Next, clearing cellular trash aggregates:

A University of Michigan cell biologist and his colleagues have identified a potential drug that speeds up trash removal from the cell's recycling center, the lysosome.

The finding suggests a new way to treat rare inherited metabolic disorders such as Niemann-Pick disease and mucolipidosis Type IV, as well as more common neurodegenerative diseases like Alzheimer's and Parkinson's, said Haoxing Xu, who led a U-M team that reported its findings March 13 in the online, multidisciplinary journal Nature Communications.

"The implications are far-reaching," said Xu, an assistant professor of molecular, cellular and developmental biology. "We have introduced a novel concept—a potential drug to increase clearance of cellular waste—that could have a big impact on medicine." _UMich News

More at the link.

Both of these developments will require a number of years to perfect and shape into useful therapies. But as noted, improved therapies in either domain would provide hope for slowing the ageing process, and for treating many of the degenerative scourges of human existence.

The SENS Foundation has worked to promote research in the seven areas pictured above. And at least partially due to the efforts of SENS, more researchers and funding agencies are picking up the same themes.

Cross-posted from Al Fin blog

Rejuvenating 100 Year Old Cells: Advances in Regenerative Medicine

"Signs of aging were erased and the iPSCs obtained can produce functional cells, of any type, with an increased proliferation capacity and longevity," explains Jean-Marc Lemaitre who directs the Inserm AVENIR team....The age of cells is definitely not a reprogramming barrier. _SD

Cell Rejuvenation via IPSC
Scientists at the Functional Genomics Institute have taken cells donated by persons older than 100 years, and reprogrammed these senescent cells into pluripotent stem cells and embryonic stem cells. These stem cells can then be differentiated into specialised cells for cell, tissue, and organ replacement therapy -- once the details are worked out.

The researchers have successfully rejuvenated cells from elderly donors, some over 100 years old, thus demonstrating the reversibility of the cellular aging process.


To achieve this, they used an adapted strategy that consisted of reprogramming cells using a specific "cocktail" of six genetic factors, while erasing signs of aging. The researchers proved that the iPSC cells thus obtained then had the capacity to reform all types of human cells. They have the physiological characteristics of "young" cells, both from the perspective of their proliferative capacity and their cellular metabolisms.


Researchers first multiplied skin cells (fibroblasts) from a 74 year-old donor to obtain the senescence characterized by the end of cellular proliferation. They then completed the in vitro reprogramming of the cells. In this study, Jean-Marc Lemaitre and his team firstly confirmed that this was not possible using the batch of four genetic factors (OCT4, SOX2, C MYC and KLF4) traditionally used. They then added two additional factors (NANOG and LIN28) that made it possible to overcome this barrier.


Using this new "cocktail" of six factors, the senescent cells, programmed into functional iPSC cells, re-acquired the characteristics of embryonic pluripotent stem cells.
In particular, they recovered their capacity for self-renewal and their former differentiation potential, and do not preserve any traces of previous aging. To check the "rejuvenated" characteristics of these cells, the researchers tested the reverse process. The rejuvenated iPSC cells were again differentiated to adult cells and compared to the original old cells, as well as to those obtained using human embryonic pluripotetent stem cells (hESC).


...The results obtained led the research team to test the cocktail on even older cells taken from donors of 92, 94 and 96, and even up to 101 years old. "Our strategy worked on cells taken from donors in their 100s. The age of cells is definitely not a reprogramming barrier." He concluded. "This research paves the way for the therapeutic use of iPS, insofar as an ideal source of adult cells is provided, which are tolerated by the immune system and can repair organs or tissues in elderly patients." adds the researcher.


...Inserm's AVENIR "Genomic plasticity and aging" team, directed by Jean-Marc Lemaitre, Inserm researcher at the Functional Genomics Institute (Inserm/CNRS/Université de Montpellier 1 and 2) performed the research. The results were published in Genes & Development on November 1, 2011 _SD

The first use of this new regenerative technology is likely to be cell replacement therapy. But as the methods for growing replacement tissues and organs in the lab are perfected, the methods should be suitable for producing cells to use in growing replacement tissues and organs for purposes of disease treatment and for treating senescence.

Cross-posted from Al Fin

Can Delaying Puberty & Extending Childhood Increase Lifespan?

Puberty seems to be arriving at earlier ages for both boys and girls. There are many reasons why puberty onset is earlier now, but most of these reasons are still unclear. The problems that arise from premature puberty include violence, higher risks of cancer and diabetes, increased behavioural problems (drugs, alcohol, delinquency etc), isolation from peer groups -- even a change in growth rates for the children of girls with premature onset of puberty.

ImageSource

...children who go into early puberty are prematurely sexualised and too immature to deal with the implications. They are more vulnerable to sexual abuse, inappropriate sexual behaviour, sexually transmitted diseases and teenage pregnancy. “It means that children develop sexually much earlier,” Stanhope says. “They are physically ready for sexual reproduction but mentally completely unready.”

Studies have shown that adolescents who go through puberty earlier are involved in more risk-taking behaviour, such as taking drugs, binge drinking and breaking the law. A premature increase in testosterone can lead to aggression in boys who lack the maturity to control impulses. “We all realise that testosterone is a very difficult hormone to learn to live with,” Stanhope says, tapping a pencil vigorously on his pockmarked table, “and if you get a rise in testosterone outside the normal physiological age, then it’s even more of a problem.”

Research published this year in the Australian and New Zealand Journal of Criminology also found increased aggression in girls who reached puberty early. In Britain the uncomfortable reality that children are becoming sexually mature earlier has been overlooked in the recent debate about the over-sexualisation of children. Instead of simply focusing on cynical manufacturers producing padded bras for seven-year-olds, perhaps we should also consider how to respond to the new reality that some girls are now growing breasts at this age.

Stanhope also points out that for women there may be long-term health problems, because early puberty increases exposure to oestrogen. According to Cancer Research UK, a girl who has her first period a year later than her contemporaries has 5% less risk of developing breast cancer in later life. “There may be an important link with breast and ovarian cancer,” Stanhope says. “The earlier a girl has her period, the longer her exposure to oestrogen and this may well have very important sequelae for oestrogen-dependent tumours. This increases her risk of breast cancer, ovarian cancer and of developing cardiovascular problems.”

Girls who reach puberty early are also more likely to develop type 2 diabetes. A 37-year-long study of 61,000 Norwegian women showed that women who got their first period at ten or 11 had a 10% higher mortality rate than those who got their period four years later. _PubertyBlues

Scientists are beginning to home in on the physiological initiators of puberty, and have found a way to delay puberty in mice. By "knocking out" a specific gene, IGF-1R, researchers have both delayed puberty and maintained normal reproductive function after puberty in these knockout mice.

Pubertal onset, initiated by pulsatile gonadotropin-releasing hormone (GnRH), only occurs in a favorable, anabolic hormonal milieu. Anabolic factors that may signal nutritional status to the hypothalamus include the growth factors insulin and IGF-1. It is unclear which hypothalamic neuronal subpopulation these factors affect to ultimately regulate GnRH neuron function in puberty and reproduction. We examined the direct role of the GnRH neuron in growth factor regulation of reproduction using the Cre/lox system. Mice with the IR or IGF-1R deleted specifically in GnRH neurons were generated. Male and female mice with the IR deleted in GnRH neurons displayed normal pubertal timing and fertility, but male and female mice with the IGF-1R deleted in GnRH neurons experienced delayed pubertal development with normal fertility. With IGF-1 administration, puberty was advanced in control females, but not in females with the IGF-1R deleted in GnRH neurons, in control males, or in knockout males. These mice exhibited developmental differences in GnRH neuronal morphology but normal number and distribution of neurons. These studies define the role of IGF-1R signaling in the coordination of somatic development with reproductive maturation and provide insight into the mechanisms regulating pubertal timing in anabolic states. _JCI

Scientists will find additional triggers for pubertal onset besides insulin and IGF-1, and some of those factors may provide a more benign approach to the delaying of puberty.

Paradoxically, IGF-1 is vital for normal development of mice, but knocking out IGF-1 receptors in certain flies and worms can increase lifespan. That paradox is still being studied.

So -- how long should puberty be delayed, if at all? If childhood could be extended for several more years without impairing the ability of the child to learn and mature psychologically, would the potential health and societal benefits be worth the postponement of sexual development of the child?

What if aging itself were to be postponed along with puberty? If total lifespan were extended by the number of extra years a person spent in childhood, would that be beneficial to society or not? What if a person could live an extra 20, 30, or 50 years -- but had to spend those extra years as a pre-pubertal child. Would it be worth it?

Those who see increased longevity as a sure path to overpopulation collapse of Earth's ecosystem, would insist upon some form of sterilisation for those who opt for longevity. In some countries, laws of that type -- mandating permanent sterilisation for anyone undergoing longevity treatments -- should be expected.

Extended pre-puberty is a form of time-limited and (probably) reversible sterilisation, so any longevity approach that also delayed puberty significantly, should not raise the hackles of those suffering from overpopulation anxiety too much. But there are likely to be a large number of objections to such treatments, all the same.

Modern societies appear to see children in a schizoid manner. Fewer children are born, so the one or two children a family does have, are cherished and pampered. On the other hand, children are seen as a hindrance to a hedonic lifestyle, an exorbitant expense and often a great bother. Overall, most children do not seem to be raised or educated very well in modern societies, judging by observable results.

While childhood is not prolonged in modern societies, an incompetent adolescence is certainly prolonged -- in many cases indefinitely. Given the choice between a prolonged childhood leading into an accelerated but prepared-for adolescence, and the current state of lifelong incompetent adolescence commonly seen in the affluent world, most Al Fin mental health professionals would choose the prolonged childhood combined with a prepared-for adolescence that leads into a responsible and competent adulthood.

Previously published at Al Fin

Methionine Restriction and QOD Feeding

The latest issue of Rejuvenation Research contains some articles dealing with dietary restriction strategies for extending lifespan.

The latest issue of Rejuvenation Research is online. You'll find a few more esoteric items on calorie restriction biochemistry, but one paper on methionine restriction is more accessible and interesting. By way of a reminder, recall that there's a fairly good argument for the beneficial effects of calorie restriction to largely stem from lowering the intake of methionine, one of the eight essential amino acids in your diet.

On Methionine Restriction, Suppression of Mitochondrial Dysfunction and Aging

Rats and mice, when subjected to methionine restriction (MetR), may live longer with beneficial changes to their mitochondria. Most explanations of these observations have centered on MetR somehow suppressing the effects of oxygen free radicals.

The other paper that caught my attention is a nice demonstration that the benefits of calorie restriction don't necessarily have anything to do with insulin-like growth factor 1, IGF-1. For those who have been following research into IGF-1 metabolism and aging, a field with at least as much interest as investigations into mitochondria and aging, that might be a counterintuitive result.

Effect of Every Other Day Feeding on Mitochondrial Free Radical Production and Oxidative Stress in Mouse Liver

It is known that dietary restriction (DR) increases maximum longevity in rodents, but the mechanisms involved remain unknown. Among the possible mechanisms, several lines of evidence support the idea that decreases in mitochondrial oxidative stress and in insulin signaling are involved but it is not known if they are interconnected.

It has been reported that when C57BL/6 mice are maintained on an every other day (EOD) feeding their overall food intake is only slightly decreased and plasma insulin-like growth factor (IGF)-1 is even somewhat increased. In spite of this, their maximum longevity is increased, analogously to what occurs in classic DR. Thus, this model dissociates the increase in longevity from the decrease in IGF-1 observed in classic DR.

...

These results support the possibility that EOD DR increases maximum life span at least in part through decreases in mitochondrial oxidative stress which are independent from insulin/IGF-1-like signaling.

_FightingAging

Various manipulations of diets in animal models should provide us with more information about aging mechanisms, as research designs become more sophisticated to tease out effective manipulations, and as collection and analysis of animal response data delves more deeply into the actual molecular mechanisms that are altered.

Update on "Understanding Aging" at UCLA

After working in obscurity and semi-respectability for almost a decade, Aubrey de Grey is finally getting the recognition he deserves. The Understanding Aging conference at UCLA is wrapping up after a full weekend of presentations.

Probably the most famous presentation of the weekend to hit the news so far, is the potential "cancer cure" being studied by Wake Forest researcher Zheng Cui, who gave a presentation yesterday at the meetings. Zheng's study involves screening 500 healthy young (under 50) adult volunteers for cancer resistance, then selecting the 100 volunteers with the strongest measured cancer resistance and taking white blood cell (WBC) donations from the 100. These WBC's would then be transfused into cancer patients to determine safety and efficacy of the treatment. The approach has proved very successful in mice. More information here and here.

Another interesting presentation was given by Trevor Marshall reporting on studies linking stem cells, cancer, and bacterial infection.

This comprehensive overview from Brian Wang allows a busy non-attendee to briefly sample the research fare of the busy weekend conference. By doing an internet search using a science search engine, you can often find full text articles by participating authors, which should give considerable background on their current research.

Aubrey de Grey's excellent introduction to SENS anti-aging research, Ending Aging, was published in 2007, but the information in parts of the book is already becoming obsolete by the rapid progress in research labs. Thanks to the energy, ideas, and fund-raising by de Grey and his colleagues, anti-aging research is finally coming out of the closet into the daylight.

Aubrey de Grey's Ending Aging

I recently had the opportunity to read Aubrey de Grey's briskly selling book, Ending Aging.

The book goes into more detail about the 7 approaches to anti-senescence discussed at the SENS website. Consider a progress report on a very important front of scientific research. Arnold Kling takes an economist's look at the book, and is intrigued:

Four years ago, I reported that de Grey foresees a not-too-distant future in which humans can reverse the effects of aging, raising the possibility of living healthy lives for hundreds of years. He has not backed away from that position, and this book, written by de Grey and his research associate Michael Rae, represents an update from his perspective. In brief, he says that

1. The latest scientific research indicates no flaws in the theory that aging can be eradicated.

2. However, getting the required techniques developed will require institutional changes relative to our current system for conducting medical research.

As an economist, I am most interested--and most qualified to form an opinion about--the second point.

...De Grey sees aging as a byproduct of an evolutionary process that takes place within the body. Mutations occur over time within your cells, sometimes randomly and sometimes stimulated by external events. This evolutionary process changes the balance between what I might call "good stuff" and "bad stuff" (here I am taking the technical caliber of the scientific exposition down several levels). Sometimes, the "good stuff" gets stronger, as when we develop an immunity to a disease. More often, however, the "good stuff" gets weaker and the "bad stuff" (like arterial plaque or pre-cancerous cells) gets stronger. It is this shift in the balance that leads to the symptoms of aging, including susceptibility to disease, which ultimately proves fatal.

Because aging is a natural outcome of the body's internal evolutionary processes, de Grey argues that the standard paradigm for fighting the diseases of aging one by one is flawed. Prevention of one disease, in the form of slowing the processes that cause it, is a doomed strategy.

...Too often, academics use their credentials to spit out biased polemics dressed up as science. Ending Aging is the opposite. It is a crash course in state-of-the-art science dressed up as a polemic. De Grey wears his passion for undertaking a war on aging on his sleeve, yet most of the book consists of scientific analysis that, although simplified to enable a layman to follow, is conscientious in reporting doubts and objections to the author's point of view.

...What de Grey is saying is that today's cautious approach to experimental medical testing significantly slows the rate of progress, which means that many people will suffer and die unnecessarily. However, those people are unseen and unknown, whereas those who suffer and die as a result of medical experiments are identifiable and visible. I think that trying to sell people on the idea of taking more risks in order to advance medical progress is not as straightforward as de Grey makes it sound

...My guess is that de Grey will have better luck if he tries to mobilize wealthy philanthropists. If instead of donating buildings to universities our billionaires would donate money for prizes that reward general-purpose medical technologies, we might not have to wait for government research to adopt a paradigm shift, which is almost surely not going to happen. Wealthy (and not-so-wealthy) philanthropists who are reading this should check out de Grey's organization SENS and look for ways to contribute both to his institute and to a prize fund.

TCS

Future research will make part of de Grey's program moot and unnecessary. Other future research will likely incorporate some of de Grey's ideas. The point is, de Grey's approach is the best one currently operating, so that if someone did have extra money he/she was thinking about donating to science, they could do much worse than to donate to SENS.

I recommend the book to anyone interested in the extension of healthy human lifespan. Getting much of the same information from the SENS website + literature searches is possible, but you wouldn't want to miss Aubrey's unique argumentative style.

Google Tech Talk May 29 '07: Aubrey de Grey

Here is de Grey at Google, speaking for an hour about the technology of healthy extension of lifespan.

Hat tip Michael Anissimov and Brian Wang.