A single drug can shrink or cure human breast, ovary, colon, bladder, brain, liver, and prostate tumors that have been transplanted into mice, researchers have found. The treatment, an antibody that blocks a “do not eat” signal normally displayed on tumor cells, coaxes the immune system to destroy the cancer cells. _ScienceMagNews

In research published on PNAS (Full PDF), Stanford researchers demonstrated the ability to successfully destroy human cancer growing in mice, using monoclonal antibodies targeted against the cellular protein CD47.

CD47 is overexpressed in many cancers, and allows the tumour cells to “fly beneath the immune system’s radar,” thus escaping destruction. By blocking CD47, the scientists demonstrated that the immune system was able to destroy tumour cells that would have been otherwise ignored.

To determine whether blocking CD47 was beneficial, the scientists exposed tumor cells to macrophages, a type of immune cell, and anti-CD47 molecules in petri dishes. Without the drug, the macrophages ignored the cancerous cells. But when the CD47 was present, the macrophages engulfed and destroyed cancer cells from all tumor types.

Next, the team transplanted human tumors into the feet of mice, where tumors can be easily monitored. When they treated the rodents with anti-CD47, the tumors shrank and did not spread to the rest of the body. In mice given human bladder cancer tumors, for example, 10 of 10 untreated mice had cancer that spread to their lymph nodes. Only one of 10 mice treated with anti-CD47 had a lymph node with signs of cancer. Moreover, the implanted tumor often got smaller after treatment — colon cancers transplanted into the mice shrank to less than one-third of their original size, on average. And in five mice with breast cancer tumors, anti-CD47 eliminated all signs of the cancer cells, and the animals remained cancer-free 4 months after the treatment stopped.

“We showed that even after the tumor has taken hold, the antibody can either cure the tumor or slow its growth and prevent metastasis,” says Weissman.

Although macrophages also attacked blood cells expressing CD47 when mice were given the antibody, the researchers found that the decrease in blood cells was short-lived; the animals turned up production of new blood cells to replace those they lost from the treatment, the team reports online today in the Proceedings of the National Academy of Sciences.

Cancer researcher Tyler Jacks of the Massachusetts Institute of Technology in Cambridge says that although the new study is promising, more research is needed to see whether the results hold true in humans. “The microenvironment of a real tumor is quite a bit more complicated than the microenvironment of a transplanted tumor,” he notes, “and it’s possible that a real tumor has additional immune suppressing effects.”

Another important question, Jacks says, is how CD47 antibodies would complement existing treatments. “In what ways might they work together and in what ways might they be antagonistic?” Using anti-CD47 in addition to chemotherapy, for example, could be counterproductive if the stress from chemotherapy causes normal cells to produce more CD47 than usual. _SciencemagNews

This approach would probably not qualify as a solo therapy, but would rather be used along with other anti-cancer therapies, to either cure a cancer or to limit its growth and spread where cure is not possible.

Researchers believe that all solid tumours may well be vulnerable to this approach.

This treatment will not be without side effects, and not all cancer patients would benefit or qualify for such treatment. But it is very promising.

H/T NextBigFuture

Al Fin Longevity

A study published this week in the Journal of Neuroscience shows that the compound epothilone D (EpoD) is effective in preventing further neurological damage and improving cognitive performance in a mouse model of Alzheimer’s disease (AD). The results establish how the drug might be used in early-stage AD patients.

…EpoD acts by the same microtubule-stabilizing mechanism as the FDA-approved cancer drug paclitaxel (Taxol™). These drugs prevent cancer cell proliferation by over-stabilizing specialized microtubules involved in the separation of chromosomes during the process of cell division. However, the Penn researchers previously demonstrated that EpoD, unlike paclitaxel, readily enters the brain and so may be useful for treating AD and related disorders.

After three months of receiving EpoD, additional tau clumps did not form in the brains of the aged AD mice, and nerve-cell function was increased compared to the AD mice that did not receive drug. What’s more, the EpoD-treated mice showed improvements in learning and memory. Importantly, the doses of EpoD that resulted in these benefits were much lower than had previously been used in Phase II clinical testing of EpoD in cancer patients. The investigators observed no side-effects — including the suppression of the immune system and peripheral nerve damage — in the transgenic mice that received EpoD. _UPennNews

Most approaches to treating Alzheimer’s dementia aim to either affect the levels of neurotransmitters in the brain — particularly acetylcholine — or to decrease accumulation of amyloid beta protein.

The idea of over-stabilising neurotubules to prevent tau tangles from forming in early stage Alzheimer’s is an intriguing approach, and dates to earlier studies attempting to discover the true etiological origins of Alzheimer’s. More from a 2011 study published in The Journal of Neuroscience:

Alzheimer’s disease (AD) pathology is characterized by senile plaques (SPs) and neurofibrillary tangles (NFTs) (Selkoe, 2001). SPs are extracellular deposits of amyloid-β (Aβ), a 3–4 kDa peptide derived from proteolytic cleavage of the amyloid precursor protein (APP) by β-site APP cleavage enzyme 1 (BACE) (Hussain et al., 1999; Sinha et al., 1999; Vassar et al., 1999; Yan et al., 1999) and the presenilin (PS)-containing γ-secretase complex (De Strooper et al., 1998; Wolfe et al., 1999). NFTs are intracellular accumulations of hyperphosphorylated tau (Lee et al., 2001). About 5% of AD cases are linked to pathogenic mutations in APP, PS1, or PS2 genes (Selkoe, 2001). Tau gene mutations are pathogenic for familial frontotemporal lobar degeneration characterized by tau pathology without SPs, indicating that tau abnormalities alone cause neurodegenerative disease (Lee et al., 2001). _Journal of Neuroscience 25 May 2011, 31(21): 7691-7699; doi: 10.1523/​JNEUROSCI.6637-10.2011

Note that researchers are still attempting to unravel the apparent multiple strings of causation involved in Alzheimer’s Disease (AD) and similar neurodegenerative diseases of the brain.

The new research involving microtubule stabilisation, was performed in transgenic mice, meaning that results in human populations using such treatments may be quite different. The fact that both amyloid placques and tau tangles are seen in pathological brain specimens from AD patients suggests that more than one treatment approach may ultimately be required for many, if not most AD sufferers.

Cross-posted from Al Fin blog

Al Fin Longevity

Number of deaths for leading causes of death
Heart disease: 599,413
Cancer: 567,628
Chronic lower respiratory diseases: 137,353
Stroke (cerebrovascular diseases): 128,842
Accidents (unintentional injuries): 118,021
Alzheimer’s disease: 79,003
Diabetes: 68,705
Influenza and Pneumonia: 53,692
Nephritis, nephrotic syndrome, and nephrosis: 48,935
Intentional self-harm (suicide): 36,909 _CDC US Leading Causes of Death

As shown above, stroke — cerebrovascular accident (CVA) — is the 4th ranking cause of death in the US. Besides mortality, there is also significant morbidity and disability associated with stroke worldwide.

Recent research at Toronto Western Hospital provides reason to hope for better drug treatments for stroke in the near future. The researchers tested a new type of drug — a PSD-95 inhibitor — in primates, in an acute stroke setting. Some of their results are pictured below.

A phase 2 clinical trial in humans was also recently completed in Ontario.

In a series of experiments, Michael Tymianski and colleagues at Toronto Western Hospital in Ontario, Canada, replicated the effects of stroke in macaques before intravenously administering a PSD-95 inhibitor, or a placebo. PSD-95 inhibitors interfere with the process that triggers cell death when the brain is deprived of oxygen.

To test its effectiveness the team used MRI to measure the volume of damaged brain for 30 days following the treatment, and conducted behavioural tests at various intervals within this time.

Monkeys treated with the PSD-95 inhibitor one hour after stroke had 55 per cent less damaged tissue in the brain after 24 hours and 70 per cent less after 30 days, compared with those that took a placebo. These animals also did better in behavioural tests. Importantly, the drug was also effective three hours after stroke.

…An early stage clinical trial in humans, run by firm NoNO in Ontario has also seen positive results. _NewScientist

Nature study abstract

PSD-95 Overview

PSD-95 complex as drug target for antidepressant development

The Role of PSD-95 and Cypin in Morphological Changes in Dendrites Following Sublethal NMDA Exposure Interesting abstract providing information on underlying factors involved.

This is a line of treatment which has been obvious for decades, but which has lacked the proper basic science backing up until now. Although PSD-95 inhibitors will not prevent all brain damage from occurring in stroke, nor will they restore damaged brain to normal function afterward, they do seem to limit the amount of damage that occurs, for each stroke.

It is a type of stop-gap measure, meant to prolong relative normal function as long as possible. More optimal developments for the future will involve better preventive measures and ways to rejuvenate damaged brain after the insult occurs. Full spectrum medical care will eventually involve all avenues of treatment, prevention, and restoration.

Al Fin Longevity

Platinum was the first precious metal to achieve recognition as an effective cancer therapy:

The first platinum based chemotherapy drug discovered by researchers was cisplatin, which forty years later continues to have applications in certain types of cancer. In that time, scientists have searched for ways to improve the anti-tumor efficacy of platinum based drugs, reducing the toxicity profile, and strengthening them against resistance by expanding the class to include several new analogues of cisplatin and putting them through clinical trials to broaden the different types of cancers against which they can be safely used. _Source

Gold has more recently been recognised to have utility in fighting cancer. Gold is being used to help locate tumours and cancer cells for radiation treatment, and is also being used in drug complexes, for its cytotoxic properties.

In the last few decades the properties of gold compounds have been of interest as potential cancer treatments. Researchers at the National University of Singapore have patented novel gold complexes for use in pharmaceuticals for the treatment of cancer.

Associate Professor Leung Pak Hing and his team have discovered that phosphine supported gold complexes have excellent anti-tumour activity and clinical trials are likely to begin in the near future.

In some cases, new technologies rely on the ability of tiny gold nanoparticles to specifically collect in a cancerous tumour by passing through the inherently leaky blood vessels attached to a tumour. So, when injected into a patient, there is a means by which a potent anti-cancer compound attached to a gold nanoparticle, can be directly and accurately delivered to a tumour whilst avoiding healthy body tissue. Such an effective drug delivery mechanism with reduced toxicity is considered to be a major step-forward. Why use gold as the delivery mechanism? Well gold has a major advantage in being a very biocompatible metal. For example, colloidal gold has been safely used for over 70 years to treat rheumatoid arthritis, and many hundreds of years as a dental restoration. _AzoNano

Even more recently, silver is being seen as a potentially effective anti-cancer material.

Previous studies have hinted that silver compounds could also kill cancer cells. So Charlotte Willans from the University of Leeds, UK, and colleagues subjected silver to the same treatment as platinum to see if they could make an effective cancer drug.

The team attached different types of carbene ligands to the silver atoms before incubating varying concentrations of the compound with breast and colon cancer cells for six days.

The silver complexes proved to be as effective as cisplatin in attacking both types of cancer cells. Complexes containing a ligand which had two bonds were more effective than those with a single bond, probably because they are more stable - meaning the compound breaks down more slowly and is active for longer (Dalton Transactions, DOI: 10.1039/C2DT12399A).

Crucially, silver is less toxic to normal cells than platinum. Willans says it is an important step in the quest for effective, non-toxic cancer treatments. _NewScientist

More on the use of silver to treat cancer

The use of precious metals to treat cancer is one more reason to value them for their intrinsic worth. In developed societies, cancer is responsible for more lost years of life than virtually any other disease.

Al Fin Longevity

Scientists at the University of Toronto have recently made a breakthrough in the control of IPS cells’ pluripotency:

Scientists have found a control switch that regulates stem cell “pluripotency,” the capacity of stem cells to develop into any type of cell in the human body. The discovery reveals that pluripotency is regulated by a single event in a process called alternative splicing.

Alternative splicing allows one gene to generate many different genetic messages and protein products. The researchers found that in genetic messages of a gene called FOXP1, the switch was active in embryonic stem cells but silent in “adult” cells—those that had become the specialized cells that comprise organs and perform functions.

“It opens the field to the fact that alternative splicing plays a really important role in stem cell pluripotency,” said Prof. Benjamin Blencowe, principal investigator on the study and a Professor in the University of Toronto’s Departments of Molecular Genetics and Banting and Best Department of Medical Research. “We’re beginning to see an entirely new landscape of regulation, which will be crucial to our understanding of how to produce more effective pluripotent stem cells for therapeutic and research applications.”

The findings were published in the current online edition of the scientific journal Cell. _Source

These are some fascinating developments, which will eventually lead to advanced therapies for diseases which are currently untreatable, such as cancers and end stage degenerative diseases of the heart, lungs, liver, kidneys, and brain.

The ability to grow replacement organs from stem cells is already being proven in animals. The ability to regenerate a badly degenerated organ in situ, using stem cells, is also being proven. According to George Church, stem cells are also the best method for making genetic improvements to organs and organisms.

BioHeart’s clinical stem cell trials in Mexico

ThermoGenesis an early commercial entrant into the human stem cell regenerative medicine industry

Al Fin Longevity

(previous session)

Matt Hirschey (Verdin Lab, UCSF-Gladstone): Lack of SIRT3 results in the metabolic syndrome. SIRT3 is a mitochondrial sirtuin (NAD+-dependent deacetylase) that is upregulated in liver upon fasting; knockout mice (SIRT3KO) are grossly normal but have trouble with lipid metabolism (specifically, beta-oxidation). Hershey identified several mitochondrial proteins involved in lipid oxidation that are deacetylated in response to fasting, in wildtype but not SIRT3KO. The knockouts are prone to developing obesity and metabolic syndrome with age.

Kate Brown (Chen lab, UC-Berkeley): Calorie restriction reduces oxidative stress by inducing SIRT3. Beginning with an invocation of the free radical theory of aging, and the observation that calorie restriction (CR) reduces oxidative stress, Brown asked whether the mitochondrial sirtuin SIRT3 could be involved in resistance to reactive oxygen species. She showed that CR induces SIRT3 expression, and that the SIRT3 protein deacetylates the mitochondrial antioxidant enzyme SOD2. Furthermore, consistent with Subhash Katewa’s talk in the first session, she demonstrated that CR reduces oxidative stress by switching from glucose to fatty acid oxidation, and that this switch requires SIRT3 activity.

(We’ve discussed SIRT3 before, most recently regarding its role as a tumor suppressor and also with respect to its relationship with exercise).

Ruth Tennen (Chua lab, Stanford): Insight into SIRT6 function at telomeres and beyond. Another member of the sirtuin family, SIRT6, is not localized to mitochondria but rather to telomeres, where it maintains telomeric chromatin in a healthy state and regulates the activity of the senescence-associated transcription factor NF-κB – for more background, see this previous post.) Tennen has shown that SIRT6 is involved in regulating the telomere position effect (TPE) – the silencing of gene expression caused by proximity to a telomere. The TPE has been implicated in age-related changes in gene expression: as telomeres shorten over time, telomere-proximal genes are aberrantly expressed — meanwhile, silencing factors are liberated to wander throughout the genome, repressing genes that should be turned on; similar logic has been applied to the relationship between DNA damage and transcriptional dysregulation.

Jue Lin (Blackburn Lab, UCSF): Telomere length maintenance and aging-related diseases. This talk described work that builds on significant progress, from this lab and others, demonstrating relationships between telomere length and stress, psychological outlook, and lifespan. Lin reviewed evidence that perceived stress is correlated with telomere length in white blood cells (consistent with previous results showing a relationship with intrusive thoughts). New-to-me data included a demonstration that people who increased omega-3 levels or made favorable lifestyle changes exhibited a slower rate of telomere shortening.

(next session)

Ouroboros

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

(^ Index)
(<– Previous session)

Talks in this session:

1. Choy: Intracellular trafficking and processing of amyloid precursor protein
2. Kown: Age-associated decline in immune function; new role of SIRT1 in regulatory T cells
3. Pan: Regulation of p53 and ageing by SnoN
4. Grueter: Disruption of the lipid synthesis gene, DGAT1, extends longevity

Regina Choy (Berkeley; Shekman lab) — Intracellular trafficking and processing of amyloid precursor protein

The talk began with a review of the proteolytic processing of amyloid precursor protein (APP) into Aß peptides. Choy emphasized that it is important to have a balance between the amyloidogenic and non-amyloidogenic pathways – a bias toward amyloidogenesis places one at risk for Alzheimer’s disease (AD).

The big question: Where is Aß being produced inside the cells? (What are the possible intracellular sites of Aß peptide production? Where is it actually happening). The approach: study of APP trafficking. The goal: Insights into regulation of Aß production and its relationship to AD.

Building on evidence that the primary site of Aß is the endosome, Choy performed RNAi knockdowns of the endosomal sorting machinery (ESCRT complexes as well as the ATPase VPS4). Knockdown of early components in endosomal sorting result in decreased Aß production, but knocking down the later components or VPS4 results in an increase in Aß production. Together with immunofluorescence results, these findings suggest that Aß production happens after APP leaves the early endosome. Surprisingly, however, APP does not colocalize with early endosome markers in the VPS4 knockdown – in fact, it ends up getting rerouted to the TGN. This raises the possibility that Aß production may happen after APP recycles through the TGN.

More beautiful immunofluorescence data followed, bolstering the recycling hypothesis and leading Choy to conclude in favor of a model in which the primary site of Aß production is in the TGN.

Hye-Sook Kown (Gladstone; Ott lab) — Age-associated decline in immune function; new role of SIRT1 in regulatory T cells

Regulatory T cells (Treg) maintain immune tolerance, i.e., they stop the rest of the immune system from attacking the body. They accomplish this by suppressing differentiation of naive cells and the activation of effector cells. This, in turn, helps to prevent autoimmune disease and graft rejection. However, Treg cells increase their activity during aging, which might make elderly people more susceptible to infection.

Treg activity is regulated by FoxP3, which is in turn modified by acetylation that is regulated by SIRT1. Kown used mass spec to identify the specific acetylation sites on FoxP3; she found three, and raising specific antibodies against the acetylated peptides.

Inhibition of SIRT1, a deacetylase, enhances acetylation of FoxP3 at a specific site in both Jurkat T cells and mouse inducible Treg (iTreg) cells. The acetylated protein is stabilized and active, promoting Treg differentiation and survival in a variety of cell culture and in vivo assays.

Thus, by downregulating the activity of Treg cells, SIRT1 promotes a more active immune system: lower iTreg activity promotes increased differentiation of naive T cells and activation of Th1, Th2 and Th17 effector cells. In older people where SIRT1 levels are lower, higher Treg activity may result in a less responsive immune system and higher susceptibility to infection.

In questions, I asked whether SIRT1 inhibition could therefore be used to prevent autoimmune disease – the short answer is “yes”; this has advantages over expanding Treg populations ex vivo, which sometimes results in loss of FoxP3 expression.

Deng Pan (Berkeley; Luo lab) — Regulation of p53 and ageing by SnoN

Starts off with a review of the cancer-aging hypothesis, i.e., the idea that the anticancer activity of tumor suppressors like p53 have a cost: apoptosis and senescence of damaged cells ultimately reduces the regenerative capacity of tissues, contributing to age-related decline in tissue function.

Pan has focused on SnoN, an inhibitor of TGFß/Smad signaling, using a knock-in mouse in which SnoN can no longer bind the Smad promoter. Using this system, he demonstrated that SnoN can function as a tumor suppressor by activating p53-dependent senescence.

SnoN can interact with the PML-p53 pathway; the SnoN protein is a component of PML-nuclear bodies, which in turn activate p53. There are several ways to activate p53: stabilization (i.e., preventing ubiquitination); antiprepression, and promoter-specific activation. How specifically is SnoN activating p53?

Using pulldown assays, Pan showed that SnoN can directly bind to p53, in a manner that does not depend on PML. This binding stabilizes p53, probably because SnoN competes with Mdm2 (which ubiquitinates p53, targeting it for destruction). The working model is that SnoN is a stress transducer that communicates information about cellular stress to the p53 pathway.

The knock-in mice showed premature aging-related phenotypes, including kyphosis and hair loss, as well as higher levels of senescent and apoptotic cells.

Carrie Grueter (Gladstone; Farese lab) — Disruption of the lipid synthesis gene, DGAT1, extends longevity

Given how much we know about fat and lifespan, it is perhaps surprising that very few longevity studies have focused on mice with modified lipid metabolism. To remedy this omission, Carrie Grueter has been studying the effect of the DGAT1 (diacylglycerol O-acyltransferase) knockout on phenotypes including lifespan. (DGAT is involved in triglyceride synthesis.)

Hypothesis: Leanness, with a concomitant improvement in metabolism, will extend longevity.

DGAT-deficient mice use more oxygen than wildtype siblings, but do not consume proportionally more food. The knockout mice are protected from the age-related increase in fat mass, as well as age-related increases in inflammation. (Not surprising since abdominal fat is associated with chronic inflammation.) The knockouts exhibit decreased serum IGF-I levels.

The payoff: DGAT knockouts live 25% longer than wildtype. There’s a cost: according to Grueter’s data, DGAT-KO have trouble lactating and therefore have decreased fecundity. Furthermore, the knockouts are bad at surviving short-term calorie restriction: half the mice fail to survive a 48-hour fast, probably because their core body temperatures plummet in the absence of stored fat to burn – the lethality can be rescued by group-housing the mice with wildtype animals or by raising the temperature to 30°C.

So in sum, the hypothesis enumerated above seems to hold, at least when calories are abundant – but when times are tough, it’s nice to have a little bit of extra padding.

(Next session –>)

Ouroboros

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.

From the mailbag, news of a new aging-related peer-reviewed journal, currently in its first issue: Pathobiology of Aging & Age-related Diseases. I haven’t had to check it out yet, but it looks like it will be of broad interest to biogerontologists from a variety of disciplines. The editorial board includes quite a few luminaries of the field, so it seems promising.

In their own words:

Aims: Pathobiology of Aging & Age-related Diseases (PBA) is a new peer reviewed journal serving as a forum for researchers to communicate pathology data as a primary scientific focus of aging; data that might be of less interest in other journals more focused on generic aging or specific scientific disciplines. We are especially interested in developing a focus for advancing the pathological basis of aging in mammalian systems, in particular the mouse and humans.

Scope: Pathobiology of Aging & Age-related Diseases is interdisciplinary in nature and covers all aspects of pathology of aging related to disease phenotypes including cancer, cardiovascular disease, neurological disorders, metabolic dysfunction, renal and gastrointestinal disorders, endocrine dysfunction, musculoskeletal conditions and skin disorders. The underlying theme is based on the sound scientific principles of the pathogenesis of aging and age-related diseases as well as intervention data with resolution of pathological endpoints. The emphasis will be on preclinical studies as well as clinical studies related to strategies developed in animal models and will be image intensive. Papers on the basic biology of aging in invertebrates will not be considered unless comparative mammalian data is also included.

We welcome Research papers, Review articles, Brief reports, Case reports, New animal models, Technical reports, Images, PhD thesis Summaries, and Commentaries.

Target groups: Anatomical and molecular pathologists, gerontologists, geriatricians, transgenic mouse geneticists, toxicologists, and scientists, veterinarians and physicians focused on basic and clinical research in cardiovascular disease, cancer, gastrointestinal disease, endocrine disorders, metabolic dysfunction, renal disease, neurological disorders including Alzheimer’s disease, skin disorders, and musculoskeletal disease.

PBA is open-access; the publisher, Co-Action Press, is a relatively new entity whose small but growing stable consists entirely of open-access journals spanning a wide range of fields.

My personal feeling is that there are probably already too many journals, mostly because I don’t think I or my colleagues actually interact with journals as entities. Mostly we just do literature searches, and choose papers to read based on titles and abstracts. The exception is when we’re submitting papers, but then the diversity of formats and author requirements creates obstacles to rapid submission (and re-submission, if necessary).

I wouldn’t mind seeing individual journals be replaced by a robust tagging system on a relatively laissez-faire neo-journal such as PLoS ONE (to allow scholars to create communities and filters on the firehose of new papers), and a little time spent teaching everyone how to set up PubMed RSS feeds. That said, if we’re going to start new enterprises, this is probably the right way to go, so good luck to PBA.

Ouroboros