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

Al Fin Longevity

“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

Al Fin Longevity

the naked mole rat has what could be the most extraordinary set of natural defenses ever found in a mammal. A mouse’s life is short and terrible—even in the lab, with plenty of food and a steady thermostat, it lasts for just three or four years at the most. A naked mole rat shows no sign of aging until it’s a quarter of a century old. Blind and plump, it skitters around in a hazmat suit of its own creation. _Slate

Naked mole rats appear impervious to radiation and carcinogens of all kinds. These naked mole rats are incredibly reluctant to get cancer. And that is not the half of it:

In 2004, Buffenstein and her students tried one of these shortcuts. They placed some mole rats in a gamma chamber and blasted their pale, pink bodies with ionizing rays. The animals were unimpressed. When I visited Buffenstein’s lab this past July, many were still alive, skittering through the plastic tubes of their basement habitat at the Barshop Institute for Longevity and Aging Studies.

Four years later, Buffenstein…infected cells from a naked mole rat with a virus designed to corrupt their nuclei with the cancer-causing genes SV40 TAg and Ras. Then she slipped those cells into a live mouse, under the skin behind its ear. If you do the same using infected material from a mouse or a rat, or even a cow or a human, the transplant quickly grows into a deadly tumor, invading nearby fat and muscle tissue. But when Buffenstein and her colleagues used cells from a naked mole-rat, nothing happened.

…Earlier this year, one of Buffenstein’s graduate students tried smearing the skin of half a dozen naked mole rats with a pair of vicious carcinogens: A synthetic compound called DMBA and an inflammatory agent known as TPA. When the same toxic pairing was applied to regular Black-6 lab mice as an experimental control, a cluster of tumors popped up within weeks. Every single mouse had cancer, and every single mouse died. The naked mole rats went on skittering through their tubes.

…Her latest assault involves pouring carcinogens down the mole rats’ throats in a last-ditch effort to induce liver or mammary cancer. But that may not work, either. For years, Buffenstein’s laboratory Rasputins have been irradiated, poisoned, and heated up; their cells dosed with every imaginable pollutant—chemotherapies, oxidative stressors, and heavy metals—with little or no effect. “You name it,” the professor says, “we tried all the kinds of toxins that are out there, and the naked mole rat seems to be very resilient and resistant.”

…The very thing that makes naked mole rats so interesting to Buffenstein—an astonishing vitality that lasts for decades—only makes her research more difficult. “You’re caught between a rock and a hard place, because they live so long that your grandchildren have to finish the studies you start.” Still, slow science may have rich rewards, and the decisions we make today—on whether to invest in new model organisms or build out the ones we already have—are sure to have profound effects on the (human) generations to come. _Slate

The above Slate article by Daniel Engber is an excellent example of good science writing. We learn about the things that make the naked mole rat intriguing as an object of study, then we learn why the biomedical funding establishment is so biased against funding studies using naked mole rats. The life of science is full of such conflicts, which can drive scientists out of the lab entirely if they cannot learn to deal with the frustrating politics and grant grubbing.

No human would want to trade places with a naked mole rat, even if it meant living 10 times longer — and in better health — than the average human. But we might want some of the naked rats resistance to cancer and degenerative change.

Human gerontologists are not trying to discover the path to immortality. They are not even trying to give humans the relative advantage in life span that the naked mole rat has over other rodents. What human scientists are trying to achieve is fairly modest — they want to find a way to delay the signs of aging for roughly seven years beyond the average:

THE TARGET What we have in mind is not the unrealistic pursuit of dramatic increases in life expectancy, let alone the kind of biological immortality best left to science fiction novels.20 Rather, we envision a goal that is realistically achievable: a modest deceleration in the rate of aging sufficient to delay all aging-related diseases and disorders by about seven years.21 This target was chosen because the risk of death and most other negative attributes of aging tends to rise exponentially throughout the adult lifespan with a doubling time of approximately seven years.22 Such a delay would yield health and longevity benefits greater than what would be achieved with the elimination of cancer or heart disease.23 And we believe it can be achieved for generations now alive.

If we succeed in slowing aging by seven years, the age-specific risk of death, frailty, and disability will be reduced by approximately half at every age. People who reach the age of 50 in the future would have the health profile and disease risk of today’s 43-year-old; those aged 60 would resemble current 53-year-olds, and so on. Equally important, once achieved, this seven-year delay would yield equal health and longevity benefits for all subsequent generations, much the same way children born in most nations today benefit from the discovery and development of immunizations.

A growing chorus of scientists agrees that this objective is scientifically and technologically feasible. How quickly we see success depends in part on the priority and support devoted to the effort. Certainly such a great goal – to win back, on average, seven years of healthy life – requires and deserves significant resources in time, talent and treasury. But with the mammoth investment already committed in caring for the sick as they age, and the pursuit of ever-more expensive treatments and surgical procedures for existing fatal and disabling diseases, the pursuit of the Longevity Dividend would be modest by comparison. In fact, because a healthier, longer-lived population will add significant wealth to the economy, an investment in the Longevity Dividend would likely pay for itself. _”TheScientist“_via_NR

Can we learn anything toward that end, from the naked mole rat? Quite possibly. But we have to be willing to put in the time and expense to learn how to transfer the lessons from that exceptional rodent to the human species.

Al Fin Longevity

Dror Sagi (Stanford; Kim lab) — Engineering a long-lived worm

If aging is an engineering problem, then we should be able to solve the engineering challenges more easily in simple systems.

By introducing genes regulation from a long-lived organism into the genome of a short-lived organism, it should be possible to add pro-longevity functions – in effect “upgrading” the short-lived animal so that it lives longer. Sagi has set out to do just that, by transferring genes from the long-lived zebrafish (4-year lifespan) to the short-lived work (4-week lifespan).

The first gene he described was the UCP2 gene, the subject of an earlier talk. Expressing fish UCP2 in the worm lowers overall ATP, and extends worm lifespan. As an important control, expressing an additional copy of the worm UCP2 under the same promoter control does not extend life.

Likewise, fish lysozyme results in lower daf-16 activity, and also extends lifespan. The fish enzyme appears to act by decreasing the pathogenesis from E. coli, an unnatural food source for the worm that causes health problems in late life.

Overall, Sagi characterized 5 well-characterized longevity pathways, testing 16 genes and getting 7 hits.

The next obvious question: Can “upgrade” genes be combined to further increase lifespan? Indeed they can: several pairwise combinations of genes combined to extend lifespan longer than either single gene alone. At some point it worked a little to well: the lifespan of the worms started getting long enough that the survival curves became unwieldy.

• Staying with the worm…

Monika Suchanek (UCSF; Kenyon lab) — The germline and somatic reproductive tissues influence C. elegans

Classically, it had been assumed that there is a tradeoff between lifespan and the number of progeny produced over the lifespan. We now know that this isn’t necessarily true; there are several examples of long-lived mutants that have a normal number of progeny (though the kinetics may be slower, which poses an issue with respect to fitness: if I live twice as long as you and have the same number of progeny but half as quickly, I will probably lose the evolutionary race).

Suchanek began by reviewing old data (like, from when I was a rotation student in the Kenyon lab: old) demonstrating that removal of the germ cells results in lifespan extension, but that this longevity enhancement requires the presence of the somatic gonad. This loss of the germline causes nuclear accumulation of the DAF-16/FOXO protein in the intestine. It is clear from several diverse pieces of data that the somatic gonad and germ line exert their effects on longevity somewhat independently.

Two other genes, daf-9 and daf-12 are required for the extended longevity of germline-deficient worms. DAF-9 is an enzyme that makes dafachronic acid, the ligand of a receptor encoded by DAF-12. Addition of dafachronic acid has no effect on lifespan of germ-cell-deficient, somatic-cell-competent cells, but it does extend the lifespan of animals that lack both germ cells and the somatic gonad.

How does the intestine know that the germ line is gone? To answer this question, Suchanek screened a “signaling sublibrary” of 1304 genes, and got 115 unique hits including several components of the Wnt pathway. Two components, mom-2 and wrm-1 (ß-catenin), are required for nuclear accumulation of DAF-16/FOXO and for the extended lifespan of germline-deficient worms. Suchanek favors a model in which germ line cells emit Wnt inhibitors.

• Finishing on a strong note…

Monique Stanfel (Buck Institute; Kennedy lab) — Ribosome Function and Aging

The Kennedy lab is interested in identifying longevity/aging genes that are conserved in yeast and worm, and then testing these in the mouse.

In both yeast and worm, deletion/knockdown of many ribosomal proteins (RPs) can extend lifespan. In yeast, most if not all of the RPs with a role in lifespan are components of the large subunit (60S). In worm, knockdowns of both small and large subunit components can increase lifespan. Three of the genes conserved between worm and yeast can be knocked down in mice.

In order to characterize translation in mouse mutants, Stanfel ran polysome gradients on liver tissue. She analyzed the fractions in two ways, looking at both ribosome-associated RNAs and at the ribosome-associated proteins.

Surprisingly, the Rpl22 gene can be knocked out and has very little effect on global translation in the mouse liver. This may be because a homologous gene, Rpl22L (“-like”) is compensating for the loss of the major species.

Knockout of another gene, Rpl29, has a larger effect on global translation, decreasing the levels of 80S ribosomes. When fed a high-fat diet, Rpl29 knockouts were protected against weight gain, and their blood glucose also remained low; furthermore, the animals were leaner than wildtype. They also resist developing cardiac hypertrophy in another assay – thus, they meet all the preliminary criteria for the time and resource investment of a lifespan study.

One approach to understanding the senescent growth arrest is to examine the factors that are required for the division of young cells and to determine whether the senescent cells are able to respond to these factors. Any defect in their response would presumably shed light on the mechanism of the growth arrest. In virtually all cell types, cell division is regulated by the presence of growth factors. Growth factors are small proteins that bind to specific receptors on the surface of cells. The receptors for growth factors contain intrinsic enzymatic activity that is activated by growth factor binding. (more…)

Animal studies support a cancer-promoting role for fat, and in humans, epidemiological data strongly suggest that dietary fat intake may be associated with incidence and mortality of cancers of the breast, colon, rectum, and prostate. There are also data implicating fat in cancers of the ovaries, uterus, pancreas, and lung, but the evidence is not as strong. There is still a debate as to whether it is total dietary fat, specific fats, or total calories that are involved in carcinogenesis. In any event, cancers of breast, colon, and prostate are highest in North America and western Europe and lowest in Asia, and are directly related to the intake of total fat in the diet even when adjusted for total calories. (more…)

Most older adults adapt successfully to the multiple developmental and social changes and late life depression that are common in late life. For those who experience distress or develop psychological symptoms, Cognitive-behavioral therapy offers an ideal treatment modality. The emphasis in cognitive-behavioral therapy on the acquisition of coping skills provides older adults with concrete strategies for dealing with areas of problematic adjustment. (more…)

Cognitive-behavioral interventions approaches to managing the distress associated with physical/somatic complaints problems show much promise. As with anxiety disorders, the treatment of somatic complaints of older clients with pharmacological interventions poses risks. Multiple drug interactions, risk of sedation leading to loss of balance or falls, and addiction are problems that come with use of medication as the sole treatment for these problems. A growing literature on alternate methods of treating or managing these problems suggests that cognitive-behavioral interventions is a promising addition to traditional treatments. (more…)

Abuse of drugs and alcohol is not uncommon among the elderly. The high rate of prescribed medication use, increased physiological sensitivity to drug effects, and the danger of interaction effects of multiple medications and/or alcohol place older adults at high risk for deliberate or accidental misuse of drugs or alcohol. In addition, some older adults turn to alcohol to help cope with stressful life events, thus increasing the risk of addiction or toxic interactions. (more…)

Research indicates that anxiety symptoms are more prevalent in elderly people than in any other age group, occurring at about twice the rate of younger adults. The types of anxiety disorders most common among the older population include generalized anxiety, mixed anxious-depressive syndrome symptoms, and phobias (often characterized by exaggerations of rational concerns). More rare are late-life onset of obsessive compulsive disorders (OCD) and panic disorders. (more…)