November 11, 2014

Scientific Prospects for Curing Aging

Joao Pedro de Magalha looks at scientific prospects for curing aging in the Rejuvenation Research Journal.

Joao Pedro de Magalha does not consider the breakthroughs in gene and genome editing that are occurring with CRISPR.

His conclusion :
At the current rate of progress, radical life extension will take centuries. A revolution in medicine will be necessary to develop the combination of therapies necessary to stop human aging in this century. If information, analytic, and synthetic technologies continue to improve exponentially, our capacity to understand biological systems will eventually reach a turning point, in which case a scientific revolution will indeed occur.

CRISPR is the revolution to enable genome editing and the bio-information revolution is happening

CRISPRs (clustered regularly interspaced short palindromic repeats) are DNA loci containing short repetitions of base sequences. Editas Medicine, a $43 million startup, aims to develop treatments that employ CRISPR/Cas to make edits to single base pairs and larger stretches of DNA. Inherited diseases such as cystic fibrosis and sickle-cell anemia are caused by single base pair mutations; CRISPR/Cas technology has the potential to correct these errors.

The Journal Science discusses the gene editing revolution from CRISPR-Cas9

CRISPR is ten to one hundred time better and cheaper than older methods of gene editing

CRISPR-Cas9 offers several key benefits over competing endonuclease technologies. First, while mega-nucleases, ZFNs, and TALENs can be thought of as bespoke single-function machines, Cas9 is basically a programmable enzyme. All that is required is a construct expressing the generic Cas9 nuclease and a set of instructions in the form of a “single-guide RNA” (sgRNA) complementary to the desired target. The system is simple and inexpensive to implement and thus more attractive to researchers who might have been skittish of ZFNs and TALENs.

The second benefit is multiplexing. Since Cas9 is guided by its sgRNA, researchers can program it with multiple guide RNAs simultaneously. Feng Zhang and George Church, writing independently in Science, have both demonstrated the ability to target two sites simultaneously and Rudolf Jaenisch has targeted five.

Jaenisch found that 20 of 96 mouse embryonic stem cell clones tested using three sgRNAs simultaneously contained NHEJ-induced mutations at all six alleles of those three genes, a 20% success rate (5). Church observed HDR-mediated repair rates in human cells of 3% and 8% using two separate sgRNAs, compared to about 0.5% with a TALEN directed at the same location (4). That’s not to say CRISPR-Cas9 is perfect. Multiple studies have documented off-site targeting when using the system, for instance, at least in its original incarnation—something that could significantly limit potential clinical applications. Researchers have developed strategies to boost targeting specificity.




Joao says "If approaches can be developed to edit the genome efficiently in adult patients, then the potential is enormous because there is evidence that at least some aspects of aging may not be irreversible at the basic molecular and cellular levels."

Nextbigfutre believes CRISPR seems like the means to achieve the gains of reversing identified aspects of molecular and cellular aging.

Abstract

Recent technological breakthroughs and our growing understanding of aging have given strength to the idea that a cure for human aging can eventually be developed. As such, it is crucial to debate the long-term goals and potential impact of the field. Here, I discuss the scientific prospect of eradicating human aging. I argue that curing aging is scientifically possible and not even the most challenging enterprise in the biosciences. Developing the means to abolish aging is also an ethical endeavor because the goal of biomedical research is to allow people to be as healthy as possible for as long as possible. There is no evidence, however, that we are near to developing the technologies permitting radical life extension. One major difficulty in aging research is the time and costs it takes to do experiments and test interventions. I argue that unraveling the functioning of the genome and developing predictive computer models of human biology and disease are essential to increase the accuracy of medical interventions, including in the context of life extension, and exponential growth in informatics and genomics capacity might lead to rapid progress. Nonetheless, developing the tools for significantly modifying human biology is crucial to intervening in a complex process like aging. Yet in spite of advances in areas like regenerative medicine and gene therapy, the development of clinical applications has been slow and this remains a key hurdle for achieving radical life extension in the foreseeable future.

Life expectancy lags actual improvement against aging because it is based upon people who are dying this year. For most people this the life expectancy for grandparents. People currently 50 would expect to live to about 90. The amount of improvement expected over 40 years.


Therapies involving gene therapy, stem cells, and synthetic biology are leading the pack in disruptive medical technologies. SENS, in fact, is largely based on the development of regenerative medicine to reverse aging. Even though our understanding of aging is incomplete, there is a finite number of human organs and components in cells and genes that can go awry with age. If there are a limited number of intrinsic mechanisms of aging, as appears likely, although it is not impossible that there are more mechanisms of aging than we think, these in theory can be ad- dressed one by one. Besides, at least some aging changes are hierarchical in the sense that they can be manipulated by pinpointing causal factors. For example, we can already reverse some forms of cellular aging in vitro, including in human cells via telomerase; it is also possible to rejuvenate yeast by expressing a single transcription factor.

If our ultimate goal is to engineer biology the same way we engineer electronics, we need a much more detailed knowledge of the basic biological components, specifically we must decipher the genome and the machines of life it encodes.

Overall, I am convinced that in silico studies and models will be one of the major approaches for tackling the complexity of biology, allowing us to better develop tailored clinical interventions. The ultimate aim is to build models of biological systems and of their dysfunction during aging and disease that are accurate enough to make predictions about which components of the system should be manipulated by interventions to improve health, including in a patient-specific basis as part of personalized medicine efforts. Because we have a large search space and experiments in aging will continue to take a long time and be expensive (at least until aging reversal experiments become mundane), predictive in silico models that decrease the number of experiments to be performed can lead to rapid progress. Although systems approaches and synthetic biology are still at an early stage and restricted to very simple models and gene circuits, and deciphering the genome is a monumental task, the encouraging aspect of these approaches is that their capacity is growing exponentially although we cannot exclude a plateau at some point.

Re-Engineering Humans for Long Life

Massive-scale genome studies promise to transform our understanding of disease susceptibility and, not surprisingly, are at the basis of J. Craig Venter’s Human Longevity, Inc. company and of other similar projects. Related efforts are focusing on identifying rare protective alleles in long-lived individuals ( e.g ., centenarians and super-centenarians) and in disease-resilient individuals. There is still a large gap, however, between understanding the genome and clinical applications. Some genes may be suitable drug targets. Yet drugs have intrinsic limitations, and aging is much harder to intervene in than most diseases because it affects multiple tissues and eradicating it likely implies redesigning life.

A crucial issue, therefore, is that even if we can predict which genes we need to tweak to retard, stop, or reverse aging of a given tissue, we will still have to replace ( i.e ., transplants with engineered stem cells) and/or modify our cells ( i.e ., edit the genome) to avoid aging. In other words, how do we go from understanding how aging derives from the genome to develop interventions to cure aging? This, I think, is the biggest hurdle in developing a cure for aging.

Although it is unknown whether all aspects of aging can be reversed in all cell types, we may be able to employ, for example, the body’s own repair mechanisms to develop therapies against age-related conditions. To stop and/or reverse human aging, we will possibly need to replace cells and rescue aging cells, and not surprisingly regenerative medicine and gene therapy are high on the few discussions of engineering rejuvenation. Nonetheless, progress in their development and clinical application has been slow in coming and their capacity is still limited. For example, in vivo genome editing in a mouse model of hemophilia helped restore function by *5%, and gene therapy for aromatic l -amino acid decarboxylase deficiency in children resulted in improvements after gene transfer. Likewise, RNAi-based approaches hold promise, for example, in a recent study showing that single-stranded RNAs can inhibit mutant huntingtin expression in the brain of mice. But the efficiency of these approaches is presently low, and, even in these single-gene conditions, a cure is not yet possible. Many Mendelian diseases remain incurable because most are caused by loss-of-function mutations, and, with a few exceptions, delivering functional proteins at specific times and to specific cells remains a major challenge. One can only speculate on the much more complex genome editing interventions required to eradicate aging: Possibly several genes will need to be edited and/or new genes added, probably in a tissue-specific fashion. (In this context, advances are also warranted to prototype new genomes accurately and inexpensively.) As such, it is easy to foresee that developing the technologies to significantly intervene in human aging is a daunting task

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