In this essay, I focus on the crucial issue of how to develop therapies to delay and eventually cure aging in adult human beings after we understand the causes of aging. Imagine that we know all the genetic and molecular mechanisms of aging, that we address the questions I previously argued as crucial for the field. Since germ therapy is too late for everyone alive, we have to correct the genotype of a significant number of our somatic cells or replace them by new ones. This is one of the most difficult steps in fighting aging and it is worth a more detailed discussion.Sections
From the Mechanisms of Aging to a Cure
Instructing the Human Body with Drugs
Cell Therapy and Stem Cells
Godseed: Changing the Soul of Man
Keywords: ageing, biogerontology, elixir of life, elixir vitae, engineered longevity, eternal youth, fountain of youth, life-extension, regenerative medicine, pharmacogenomics
From the Mechanisms of Aging to a Cure
Although so far the underlying mechanisms of aging remain largely a mystery, as detailed elsewhere, it is reasonable to expect that we will eventually understand the human aging process. Possibly during this century, we will know which genes determine rate of aging and we will know what changes occur in a human being from ages 30 to 70 to increase the chances of dying by over 30-fold. Yet even if researchers fully unravel the aging process, even if researchers identify the causal molecular and cellular mechanisms responsible for human aging, such breakthroughs will not necessarily lead to a cure for aging. After all, HIV was identified as the cause of AIDS roughly 30 years ago and, though there has been progress and new treatments, we still cannot cure AIDS (Gallo and Montagnier, 2003). To delay aging, not to mention to stop or reverse the human aging process, will be a monumental task.
A disease, any type of disease, is a time-dependent change in the body that leads to discomfort, pain, or even death. Therapies aim to delay, stop, or reverse those changes from occurring either by large-scale interventions, such as surgery, or by transmitting the necessary information to the body. For example, a bacterial infection may be reversed by penicillin, which can be seen as an information vector that disrupts the bacterial wall, thus killing the bacteria and reversing the disease state. Though they have a physical, biochemical basis, most pharmaceutical interventions can be seen as information vectors transmitting simple instructions that are intended to delay, stop, or reverse the time-dependent changes related to a given pathology. Not only antibiotics, but painkillers, corticosteroids, anti-depressants, and a thousand more products fit this description. Yet present therapies transmit relatively simple instructions: a painkiller may "tell" the brain to reduce its transmission of pain information and a corticosteroid may "tell" the immune system to diminish its response. Curing aging, however, will no doubt require the transmission of much larger amounts of information to the body.
Aging is a "sexually transmitted, terminal disease" that can be defined as a number of time-dependent changes in the body that lead to discomfort, pain, and eventually death. We still do not know whether aging derives from changes in a specific organ or if there are intrinsic age-related changes in each tissue that are independent of one another, as discussed elsewhere. Maybe there are organs that age faster than others or that are more important. For instance, it is clear that aging of the brain must be a top priority, as debated previously. Nonetheless, it appears that in order to cure aging we will need to target multiple types of cells and possibly address different types of molecular damage and malfunction. That is why, in spite of progress in artificial organs (e.g., Suga et al., 2011), organ transplants are unlikely to be the solution for aging, and at least not a definitive cure. The future of medicine is not in large-scale interventions but in smaller, less invasive but more precise therapies. The solution to aging is not in addressing individual age-related pathologies but rather in information vectors able to instruct our body to become young again.
To slow, stop, and reverse human aging we will likely require three steps: 1) remove damaged or inactive molecules and cells; 2) restore function to several molecules and cells by repair or replacement; 3) modify the genetic program to prevent the aging process from continuing. These interventions are what we will most likely need to balance the body's chemical reactions and molecular structural changes that become disrupted as we age. But how can we transmit such massive amounts of information to our body?
Instructing the Human Body with Drugs
Most pharmaceutical interventions are composed of compounds or biomolecules usually transmitting a single signal to the body: acetyl-salicylic acid, also known as aspirin, the anti-depressant fluxetine, hormones like growth hormone, etc. Novel developments in chemical genetics, chemogenomics and high-throughput screening are allowing the development of small molecules that target specific genes and pathways, including in the context of aging (de Magalhaes et al., 2012). A number of small molecules can activate or repress specific proteins (Peterson et al., 2000; Kuruvilla et al., 2002). With advances in technology it might be possible to develop compounds that target all or at least most genes in the human genome. If so, this would be a tremendous step in biomedical research in general and particularly in the development of therapies against disease, such as aging. Nonetheless, the number of human genome targets of approved drugs is in the hundreds with many drugs having multiple targets while others have unknown mechanisms of action (Overington et al., 2006). Besides, certain types of protein may not be amenable to drug development and the recent woes of the pharmaceutical industry (e.g., Sams-Dodd, 2005) suggest that developing specific drugs targeting most human genes is unlikely to occur in the foreseeable future.
Another problem with drugs is that the simple instructions these compounds deliver to our cells are unlikely to be adequate to cure aging. Assuming aging has, to a large degree, a genetic basis, as debated before, then to cure aging will require technologies that are not yet available. To give an example, there are dozens of inherited diseases originating in single genes for which there is no cure simply because we lack the technologies to turn on and off human these proteins in vivo. Since curing aging will require us to transmit large amounts of information to the body, new technologies will be necessary. Below, I will first give a brief overview of the most promising technologies to address this problem: gene therapy and single-gene interventions, cell therapy and stem cells, and nanotechnology. Afterwards, I will attempt to foresee how we can cure aging based on these technologies and what breakthroughs are still necessary.
Gene therapy has been hailed as a major tool to deliver information, in this case genes, to the human body (Lyon and Gorner, 1995; Kay, 2011). Although genes can be injected directly into the body (Symes et al., 1999; Bersell et al., 2009), most gene therapy methods involve the use of a vector for the specific purpose of inserting DNA into cells. Viruses are the most widely used vector and several experiments have already shown the power of this technology. In one exciting discovery, virus-induced expression of IGF-1, a growth factor mentioned in another essay, reversed age-related changes in the skeletal muscle of mice; increases of almost 30% in strength were observed in treated old animals when compared to controls (Barton-Davis et al., 1998). If aging may be reversed by the expression of key genes then gene therapy holds great promise. Neuronal death has also been delayed by the introduction of a single gene using the herpes virus (Antonawich et al., 1999), reversal of age-associated neural atrophy was achieved in monkeys by gene therapy (Smith et al., 1999), and the phenotype of patients with hemophilia was improved with gene therapy (Nathwani et al., 2011).
Gene therapy is promising but limited in scope due to the inherited "bandwidth" constraints of the technique. Large-scale genetic engineering is already possible in embryos (Chan et al., 2001) and maybe our grandchildren will be born without aging. But since germ therapy is too late for anyone reading these lines, present-day gene therapy has a number of limitations. The main one is that viruses cannot deliver much genetic information. A typical virus can carry up to a few thousand base pairs with some viruses being able to in the dozens of thousands base pairs. This pales in comparison to the three billion base pairs in the human genome, though of course over 90% of the genome is "junk." Maybe it is possible to use a combination of viruses but there are other problems. Viral vectors can stably integrate the desired gene into the target cell's genome but the gene's integration may occur at oncogenes, causing cancer. Efficiency of gene therapy is also low, meaning that only a small percentage of target cells are usually affected. An immune response against viruses or transgenes may also occur and is a major problem in gene therapy (reviewed in Kay, 2011). The immune response could even be fatal as in the famous case of Jesse Gelsinger. At present, virus-based gene therapy does not appear adequate to cure aging for not only is its safety dubious but its efficiency is low and the amount of genetic information viruses can carry appears largely insufficient.
In addition to viruses, it has also been proposed that certain bacteria can act as vectors in gene therapy. The major advantage being that bacteria can transport larger amounts of information and still be able to change the genome (Theys et al., 2003). As with viral-induced gene therapy, the immune response is a major problem. Some promising results have emerged from cancer treatments but it is dubious bacterial-based vectors will become a solution to aging within a near future due to safety concerns. Non-viral synthetic vectors for targeted gene delivery have also shown promise in targeting cancer (e.g., Zhou et al., 2011), but much work remains to optimize these vectors for clinical studies and increase their "bandwidth".
The above examples of gene therapy entail using viral vectors to express certain genes. In parallel, RNA interference or RNAi can be used to inactivate gene. Tiny double-stranded molecules of RNA can be designed to block a given target gene (Tuschl, 2002). For example, it has been proposed that blocking the action of the gene responsible for Huntington's disease may prevent the onset of this disease. RNAi can thus be seen as another type of information that can be delivered to the body, though developing suitable delivery methods remains a major hurdle. RNA oligonucleotides can be injected directly or a vector--often a virus--can be used to transmit the RNAi to the body (Davidson and McCray, 2011). Of course there are limitations in the use of RNAi but if specific genes have to be turned off at specific times to cure aging, RNAi appears a promising solution. For instance, oncogenes appear to be activated during aging, so it is possible that genes fostering aging, gradually leading to a decrease in viability, emerge during aging. For these, RNAi and "classical" single-molecule-based pharmaceutical interventions appear a viable solution (Haseltine, 2004).
Cell Therapy and Stem Cells
Gene therapy and RNAi are limited by their low efficiency and by the low number of genes they can affect in cells. One way to overcome this limitation is by replacing the cells themselves, a process known as cell therapy. Cells can be genetically engineered in vitro prior to be used for treatments. Since there are few theoretical restrictions as to the number of genetic modifications cells can endure before being injected into the body, cell therapy has a greater "bandwidth." For example, in an experiment aimed at treating the immunodeficiency disease SCID-X1, cells from the immune system were extracted from a patient, genetically engineered, and inserted back again with encouraging results (Cavazzana-Calvo et al., 2000); the same procedure has also been proposed to treat AIDS (Kohn et al., 1999). A number of technical hurdles remain, though, since creating and engineering cells for treatments is a complex process that still requires much more research.
One growing area of great medical potential involves stem cells (Snyder and Loring, 2005). A stem cell is a sort of "unprogrammed" cell that has the potential to become any type of cell in the organ or even in the adult body. As detailed elsewhere, aging has been linked to an age-related inability of stem cells to replenish mature cells and so therapeutic interventions that enhance stem cell functional capacity might ameliorate the age-associated atrophies of several organ systems (Donehower, 2002). More importantly, there are now techniques available to create patient-specific undifferentiated stem cells. With nuclear transfer techniques such as those that created Dolly (Wilmut et al., 1997), it is now possible to generate embryonic stem cells from an adult (Cibelli et al., 2002; Hwang et al., 2004 & 2005). In theory, it is possible to genetically modify these cells according to needs, differentiate them into the necessary tissue or organ and then implant them to treat age-related diseases, a procedure called therapeutic cloning (Cibelli et al., 1998; Lanza et al., 1999). Since these cells are genetically equal to the patient's there are few or no problems of immune incompatibility. Moreover, to avoid ethical concerns regarding the use embryonic stem-cell research, one technique called induced pluripotency (iPS) allows adult cells to be transformed into pluripotent cells using only four defined factors; in theory such iPS cells can be later derived into any type of tissue (Takahashi and Yamanaka, 2006). This revolutionary technique permits the generation of embryonic stem cells from an adult. iPS appears to rejuvenate cells to some degree (Suhr et al., 2010) and even cells from centenarians appear to be rejuvenated (Lapasset et al., 2011).
The ability of stem cells to regenerate virtually all types of tissues holds great promise (Krause et al., 2001). In theory, it is possible to create practically all components of a human being in the lab and then replace the patient's organs and tissues one by one. For example, stem cells have been used with success against heart disease (Orlic et al., 2001; Bolli et al., 2011) and to repair damage to the brain (Bjorklund and Lindvall, 2000) and spinal cord (Liu et al., 2000). Blood- and marrow-derived stem cells have been used successfully in some autoimmune and cardiovascular diseases (Burt et al., 2008). Besides, stem cells are incredibly versatile: transplantation of mesenchymal stem cells into the bone marrow shows that they can travel through the body and become bone or muscle cells depending on the needs (Horwitz et al., 1999). Interestingly, mesenchymal stem cells transplanted from young donors extends lifespan in mice (Shen et al., 2011). Taken together, these experiments demonstrate how a small subset of cells can impact on whole organs by fostering regeneration, how a few tiny cells can transmit massive amounts of information to the human body.
Harvesting and/or preparing stem cells for treatments is complex and much work remains to optimize protocols and avoid side-effects, so stem cells are not yet suitable for anti-aging treatments. Therefore, much more research is necessary but the basics for using these techniques are known and we can expect more practical applications to emerge in a near future. The ability stem cells have to sprout regeneration, repair tissues, and release tailor-made factors makes them excellent candidates for anti-aging therapies.
An adult human, once a tiny cell, is a self-assembling machine made of trillions of microscopic components. Roughly, a human being consists of ~7 x 1027 atoms and ~105 different molecular species, mostly proteins. Genes and proteins can be seen as organic nanostructures working with molecular precision to form complex components, such as cells. The concept of nanotechnology, first proposed by Richard Feynman and later developed by the pioneering work of Eric Drexler, is that our ability to manipulate matter and energy at smaller scales--one billionth of a unit is called a nano--will increase until we reach and surpass our own biological nanostructures (Drexler, 1986; Wiley, 2005). One key concept in nanotechnology is the molecular assembler, a machine capable of assembling other molecules given a set of instructions and the necessary resources. Ribosomes, the sites where proteins are built based on the instructions of the genes, are the only known molecular assemblers. A man-made molecular assembler capable of building molecule-scale machines to guide specific chemical reactions would allow the construction of devices with atomic precision capable of a myriad of functions.
In theory, nanostructures can be built to drive chemical reactions capable of reversing aging by reversing chemical reactions and damage that occur as we age. The goal of nanotech-based therapies would be to build the necessary nanostructures to reverse age-related changes with the minimal perturbation. For example, damage to the DNA increases with age. Even though it is debatable whether this is an effect or a cause of aging, it appears likely that if we could build nanostructures to reverse these changes it could at least prevent some age-related pathologies like cancer. Cells already features several of these nanostructures as part of their DNA repair machinery. Enhancing it with novel nanostructures could thus reverse this form of damage. The applications of nanotechnology are multiple and it is not possible to describe them all here, but one possible application would be to design bacteria, viruses, or even stem cells to perform large-scale gene therapy without being attacked by the immune system. For example, by taking the viral nanostructures for integrating foreign DNA into host cells and apply them to stem cells (Freitas, 2003). Simple nanofactories have also been proposed to fight disease (Leduc et al., 2007). One more advanced proposal is the design of nanites, submicroscopic robots that could fit inside cells and perform medical functions from sensory functions to killing viruses and even repairing macromolecular damage (Wiley, 2005).
Nanotechnology holds great expectations and promises (Kurzweil and Grossman, 2004). The greatest problem is that, so far, nanotechnology, at the level described above, is almost exclusively theoretical without any clinical or medical trials. Even so, nanomachines aimed at correcting molecular defects for which there is no natural tool--e.g., removal of lipofuscin, also called age-pigment--may be necessary (Freitas, 1999).
Godseed: Changing the Soul of Man
"The godseed will take over the programming of the DNA."
David Zindell in "Neverness"
The ultimate aim of research on aging is to create what David Zindell called godseed, a molecular entity capable of reversing the molecular and cellular changes that occur as we age and capable of changing the genome of our cells to prevent aging from happening again. Initially, the godseed will need to transmit a signal to drive regeneration, as happens in some of the apparently non-aging animals described before. It may even be the case that tissue regeneration will eliminate damaged molecules and senescent cells while at the same time restoring function. Otherwise the godseed will have to include ways of eliminating nonfunctional nanostructures and cells while at the same time restoring youthful vigor. Afterwards, the regenerated tissue will need to be prevented from aging again, probably by including the necessary instructions in the godseed together with the instructions ordering regeneration (Fig. 1).
Figure 1: A human is aged because of a decrease in the functional capacity of the body plus the accumulation of damage--though both could be linked. Both these processes occur at a molecular and cellular level and lead to age-related pathologies either together or independently. To reverse aging, the godseed will first need to eliminate the damaged structures: RNAi may prevent these from being produced while nanostructures from drugs to biomolecules may eliminate the damage. For restoring function the most promising method appears to involve stem cells, which can also contribute to eliminate damage. Once the body has been rejuvenated it may be necessary to prevent aging from occurring again. If the genetic program was not changed in the previous phase, then the godseed will need to modify the genetic program either by gene therapy, stem cells, or even novel nanostructures. Afterwards, aging is cured.
From a technological perspective, the godseed may well entail a combination of the techniques presented previously: a mix of RNAi to prevent the expression of certain genes and gene therapy either in vivo or ex vivo to express other types of genes and create the stem cells that will transmit the massive amounts of information necessary. The goal is to "tell" the body to regenerate. In addition, even if we do not know in detail how to reverse all age-related changes and pathologies, we may address specific pathologies through conventional therapies. For instance, to rejuvenate the immune system we will need to prevent the thymus from degenerating and so specific interventions will be necessary. Eventually, novel nanostructures may allow us to reverse specific age-related degenerative changes (Freitas, 1999). Yet we will not need mature nanotechnology for building the godseed. It is impossible to say if man-built molecular assemblers will emerge in 10, 50, or 500 years from now, so we should not, and need not, depend upon nanotechnology to cure aging. As such, the core of the godseed will likely consist of genetically-modified stem cells.
One specific case is the brain, the source of our consciousness. Again, the primary strategy should be to foster regeneration and the reversal of age-related changes. Though future technological developments are hard to predict, it appears dangerous to use viruses or bacteria as vectors for gene therapy in the brain, so again stem cells hold the greatest promise. Though these have "bandwidth" limits, non-invasive methods to express exogenous genes in the brain are being developed and may be useful to express specific critical genes (Shi and Pardridge, 2000). Exosomes vesicles are one emerging area of research and have already been used to deliver RNAi to the mouse brain (Alvarez-Erviti et al., 2011).
To design and control the godseed we will need massive information systems: synthetic biology and whole genome engineering aim to allow us to program cells and genomes as if they were computers (Hasty et al., 2002). The goal is to convert information into gene networks designed to perform any task conceivable. Research is already been conducted in how to program stem cells to suit our needs. As mentioned earlier, several species such as reptiles, lobsters, and birds feature advanced regenerative capacities and appear not to age. Deriving information from these species to devise ways to re-built the human genome to avoid aging may be feasible (de Magalhaes and Toussaint, 2004b). In another example, work is being conducted to attempt to implement the advanced regenerative capacity of amphibians in mammals (Brockes et al., 2001). Synthetic biology and information systems will be the "glue" that binds all these fields together and allow us to design, regulate, and apply the godseed.
In a sense, to cure aging we will need to increase the bandwidth with which we send information to our cells. godseed need not be anything besides present technologies with more powerful and sophisticated features. If most of these technologies already exist what remains is an engineering problem of making them work according to our needs. Namely, we must: 1) develop therapies based on stem cells for tissue regeneration; 2) implement synthetic biology to control stem cells; 3) improve the safety, efficiency and accuracy of RNAi and gene therapy; 4) learn more about regeneration and what signals are involved in each tissue. Lastly, to apply whole genome engineering to aging we need to know, of course, where to act. That is, what causes aging in humans, what makes us gradually weaker and more vulnerable, but that is not the subject of this article--it is discussed elsewhere.
The most promising strategy to cure aging is to stimulate the body's own regenerative capacities, to "tell" the body not to age. As discussed elsewhere, biology is becoming an information science and intervening in aging is primarily a question of transmitting the right information to the body. godseed may well be stem cells engineered by synthetic biology and coupled to nanostructures. It may also be worthwhile to modify stem cells to change the DNA, which may be necessary to avoid aging in non-dividing tissues. Ironically, we could even make the godseed, or some of its nanostructures, endure senescence after the body is rejuvenated. Most of the molecular mechanisms for such functions, although not completely understood, exist. What is necessary is research to solve all the engineering problems we still face. The godseed is not just a utopia but an achievable goal that we can build within a, hopefully, reasonable future. We would then become gods of our bodies, making aging a sad past tale.
Notice: This is an adapted and updated version of a chapter entitled "The Dream of Elixir Vitae" that appeared in the book The Scientific Conquest of Death: Essays on Infinite Lifespans.
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