How do I knock off thirty years from my age?

Faust, the protagonist in Johann Wolfgang von Goethe’s famous play, poses this question to Mephistopheles in the chapter Hexenküche (Witches’ kitchen). Mephistopheles provides some pretty good advice – considering that he is the devil and this fictitious exchange takes place in the dark Middle Ages:

Begib dich gleich hinaus aufs Feld,

Fang an zu hacken und zu graben

Erhalte dich und deinen Sinn

In einem ganz beschränkten Kreise,

Ernähre dich mit ungemischter Speise,

Leb mit dem Vieh als Vieh, und acht es nicht für Raub,

Den Acker, den du erntest, selbst zu düngen;

Here is the paraphrased essence of the devil’s advice: Seek out a life of moderation, stop being lazy, exercise regularly by ploughing the field and avoid unhealthy foods!

How does the great scholar and scientist Faust respond to these commonsense suggestions?

Thanks, but no thanks. Faust does not like manual labor and is quite happy with his current lifestyle, so he instead opts for plan B – a magic youth potion.

Nearly two centuries after Goethe’s Faust was first performed, our quest for reversing the aging process continues. The magic potion which reverses aging continues to be as elusive as ever, but aging research has made substantial progress during the past few decades. One biological definition of aging is the gradual decline in function observed over time. Humans experience this age-related decline at a whole body or organ level such as memory loss or weakening of muscle strength, but aging also takes place in individual cells. Cellular aging or cellular senescence describes a form of “exhaustion” to the point where cells can no longer divide and a disruption of normal cellular activity. A substantial amount of scientific data suggests that the aging of individual cells plays a central role in the general decline of function in our muscle function, blood flow or metabolism which occurs when we grow older. But understanding cellular aging will not only unlock some of the mysteries of “healthy” aging, it may also help us understand and prevent certain age-associated diseases such as heart disease or cancer.

One of the central mechanisms responsible for the aging of cells is the shortening of telomeres. Telomeres are repetitive DNA sequences at the ends of chromosomes which act as protective caps. Every time a cell divides, its chromosomes undergo a doubling process so that the two daughter cells receive equal amounts of DNA. During the DNA replication and the separation of the newly formed chromosomes, small chunks of DNA are trimmed off at the end of the chromosomes. By having protective telomere caps, the shortening process only affects the telomeres and not the essential gene-encoding parts of the chromosome.

When cells in a tissue are damaged then their neighboring cells or reservoirs of regenerative stem cells and progenitor cells have to kick in, divide a replace the damaged cells. Having long telomeres would allow these regenerative neighbors to keep on dividing and restoring the tissue, whereas short-telomere cells would have to give up early on because their protective telomere caps would dwindle. Regenerative cells such as stem cells are frequently called upon to divide and this is why it is a good thing that these regenerative cells tend to contain high levels of an enzyme called telomerase which helps prevent the shortening of the telomeres. Telomerase thus acts as an anti-aging enzyme. The roles of telomeres and telomerase in cellular aging were first uncovered in the 1980s and 1990s by the pioneers Elizabeth Blackburn, Carol Greider and Jack Szostak, who all shared the 2009 Nobel Prize in Physiology or Medicine for  “the discovery of how chromosomes are protected by telomeres and the enzyme telomerase“.

At the 64^th Lindau Nobel Laureate meeting, Elizabeth Blackburn reviewed the history of how she and her colleagues identified the role of telomeres and telomerase in the cellular aging process, but also presented newer data of how measuring the length of telomeres in a blood sample can predict one’s propensity for longevity and health. It makes intuitive and theoretical sense that having long telomeres would be a good thing but it is nice to have real-world data collected from thousands of humans confirming that this is indeed the case. A prospective studycollected blood samples and measured the mean telomere length of white blood cells in 787 participants and followed them for 10 years to see who would develop cancer.  Telomere length was inversely correlated with likelihood of developing cancer and dying from cancer. The individuals in the shortest telomere group were three times more likely to develop cancer than the longest telomere group within the ten year observation period! A similar correlation between long telomeres and less diseasealso exists for cardiovascular disease.

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In 1996, Charles Sawyers designed early clinical trials for one of the first drugs aimed at a cancer-specific genetic mutation. The drug was imatinib, the cancer was chronic myeloid leukaemia and Sawyers — a clinical oncologist at the Memorial Sloan Kettering Cancer Center in New York — saw patients who had been debilitated by the disease rapidly improve when given the medicine. “It was unbelievably satisfying,” he says.

Unfortunately, he then saw many of those cancers come roaring back as they became resistant to the drug.

The experience with imatinib has given cancer biologists mixed messages. The medicine, now marketed by Novartis in Basel, Switzerland, as Gleevec or Glivec, highlights the potential of personalized medicine. Figuring out what mutation caused the disease and designing a drug to target it was a technological triumph, and it was followed by two further drugs to combat the emerging drug resistance.

But treating cancer by chasing mutation after mutation with drug after expensive drug is not a sustainable model — not least because few cancers other than leukaemia have simple, known genetic causes. “When we know the mutations and can get to a treatment strategy it’s exciting,” says Sawyers. But so far in the age of gene sequencing, he adds, “we’ve grabbed the low-hanging fruit”.

Biologists now know a huge amount about cancer — much more than they did even ten years ago. About 500 genes have been implicated in the disease, and the list is growing. There are also about 100 approved cancer drugs, some of which, like imatinib, specifically target mutations in those genes, on top of older therapies such as surgery and radiation.

But all this knowledge is not enough: even in countries where people have access to the newest therapies, improvements in death rates have slowed. Up to half of cancers could be prevented by changes in diet and exercise, encouraging people to stop smoking and eliminating environmental risks such as pollution, but other gains will be harder. To conquer cancer, researchers will need to answer some basic scientific questions. Here, Nature looks at three of the most pressing.

How can drug resistance be overcome?

To combat resistance, researchers are studying the cancer genome, coming up with new ways to design drugs, concocting combination therapies — and even looking back to Darwin’s theory of evolution.

“Seen through a Darwinian lens, the tumour is an ecosystem, a mixture of cells that are continuously mutating,” says Paul Workman, head of cancer therapeutics at the Institute of Cancer Research in London. “You put into that mix a very strong selective pressure, which is the drug.” At that point it becomes survival of the fittest. Many cells die; others use a combination of strategies to survive and thrive. These may include producing protein pumps that flush the drug out, increasing the rate of DNA repair or using an alternative molecular pathway to restore whatever function the drug blocks. Targeted drugs contribute to the genetic complexity: “These therapies themselves may be driving tumours to become more heterogeneous,” says Charles Swanton, a medical oncologist at Cancer Research UK’s London Research Institute.

A better understanding of the underlying genetic diversity of tumour cells may help researchers to work out how to tackle drug resistance. Swanton and others are therefore exploiting ever-faster and cheaper DNA-sequencing technologies. So far, Swanton says, it looks as though every tumour has a set of core mutations that are shared by all its cells. He calls these the tumour’s ‘trunk’. Subpopulations of cells within the tumour have their own unique sets of shared mutations; he calls these subpopulations ‘branches’. Therapy prunes some branches while sparing others, which then repopulate the tumour.

Researchers are now trying to look at tumour evolution in patients. One study, called TRACERx (Tracking Cancer Evolution through Therapy), will allow Swanton and a large group of collaborators to observe 850 people with lung cancer from diagnosis through therapy. Biopsies are taken from multiple spots within tumours both before and after treatment, then analysed by sequencing the parts of the tumour genomes that code for proteins. Comparing these biopsies should identify which mutations are associated with drug resistance. These kinds of studies may help geneticists to write what Swanton calls “an evolutionary rulebook of cancer” that can be used to predict tumour evolution without having to do repeated sequencing studies to get future patients on the right therapies.

Other researchers caution that genetics will provide only part of the picture of tumour heterogeneity and drug resistance. Variations in how tumours use these genes — the way they are regulated and expressed — also enable tumours to develop drug resistance. “Cells that are not intrinsically resistant to a drug will rewire their circuitry during treatment to become resistant” without any genetic changes at all, says cell biologist Joan Brugge at Harvard Medical School in Boston, Massachusetts.

Even without a full understanding of the way that tumours evolve in the face of chemotherapy, researchers are coming up with ways to overcome resistance. Using a combination of drugs can reduce a tumour’s options. Here, scientists take inspiration from the success of the antiretroviral cocktails that keep HIV in check. Like cancer, HIV has tremendous genetic diversity and evolves rapidly, but the right cocktail of drugs has transformed HIV infection from a death sentence for many into a manageable, long-term condition. Cancer presents a tougher challenge. HIV has just nine genes, compared with our approximately 20,000, making human cancer cells much more complex. Researchers are still trying to figure out how to make smart combination therapies that really work.

James Doroshow, head of cancer treatment and diagnosis at the US National Cancer Institute (NCI) in Bethesda, Maryland, believes that the best way to figure out combination therapies is to test the possibilities through brute force. The NCI has been testing 5,000 drug combinations against 60 cancer cell lines in vitro; promising candidates are then screened for toxicity in mice. The results have not yet been published, but Doroshow says that new and unexpected combinations are showing up.

Workman’s group is using computer models of gene networks to sort through thousands of possible drug combinations and genes to find likely synergies. He agrees that combination therapy is the only way to overcome resistance, but thinks that new drugs are also needed. He estimates that just 5% of known cancer genes are targeted by drugs. “If we can’t make drugs against the other 95%,” he asks, “how on Earth are we going to build the combination therapies that will lead to a cure?”

To make matters more difficult, some cancer-causing mutations work by silencing the tumour-suppressor genes that normally help to stop tumours from forming. Developing a drug to block the absence of something is a major challenge, says Workman. And some of the genes associated with cancer make proteins whose structures are unknown; without the structure, chemists have nothing to go on. Many cancer genes therefore remain, for the time being at least, untargetable.

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In a collaboration involving 13 institutions around the world, researchers have broken new ground in understanding what causes autism. The results are being published in Cell magazine July 3, 2014: “Disruptive CHD8 Mutations Define a Subtype of Autism in Early Development.”