Turning Back the Clock
"No problem can stand the assault of sustained thinking."Voltaire
Previously, I argued how real anti-aging medicine does not yet exist. In this speculative essay, I debate how gerontology may progress with the aim of developing true anti-aging therapies that not only considerably delay human aging but may actually cure aging.Keywords: ageing, antiaging, biogerontology, functional genomics, geriatrics, immortalism, life span, neurodegeneration, neuroscience
From Knowledge to Therapy
". . . the general who wins a battle makes many calculations . . ."Sun Tzu in "The Art of War"
As previously mentioned, I care about understanding the aging process for human benefit, to develop biomedical interventions that can delay aging in people and improve their health. It is possible that some genes and interventions, like klotho, IGF-1, and CR, can be used to develop anti-aging therapies, as debated before, but even in the best case scenario such therapies will not cure aging and will not radically improve our lifespan--e.g., it is doubtful that the 50% increase in mouse lifespan due to CR can be extrapolated to healthy people, as detailed previously. So what scientific approaches are more suited to cure aging?
Unfortunately, the development of true anti-aging interventions is hindered by the little we know about the mechanisms of aging. As argued by others (de Grey, 2003), however, we do not need to learn how a car works in order to drive it, and so maybe we do not need to learn everything about aging to cure it. But what exactly do we need to know? With curing aging as the ultimate goal, and based on the model systems available, I believe there are two general strategies.
Opinions diverge, and there are different methods available, but I feel that the two most important questions in the field of aging are: 1) what controls rate of aging among mammals; in other words, why does a mouse age 30 times faster than a human being; 2) what chances in a person from age 30 to age 70 to increase the chance of dying by roughly 30-fold? Addressing these two questions would give us the basic knowledge to start thinking about therapies against the aging process as a whole. By knowing what mechanisms control the pace of age-related debilitation we will know which pathways we need to target to delay aging. Likewise, by identifying the differences between young and old persons that so markedly increase the mortality we may find mechanisms that we can target through therapies, even if discriminating between causes and effects of aging will continue to be troublesome.
At present, we know almost nothing about 1) and very little about 2). The little we know about the changes people endure as they age come from studies at the level of tissues and organs, as described before. That is, we know of specific age-related declines but we do not know why those happen, what is the underlying mechanism causing these events. At a cellular and genetic level, we know very little about the aging process, though a few genes have already been identified that can modulate aging in model systems. Therefore, gerontologists must aim to answer to these questions and then hopefully we can start thinking about more powerful therapies (Fig. 1).
Figure 1: Methodologies for studying human aging. Variation is the basis for studying any phenomena and aging is no exception. On one hand we may use a comparative biology approach to understand why different species age at different paces. On the other hand, we may study the changes people, or animals, endure while they age. For instance, with current high-throughput technologies such as DNA microarrays we can study the expression of thousands of genes as humans, or animal models, age--other technologies could, of course, be adequate. Notice how the area of the circles decreases as we study species progressively more distant to humans, since it is expected that species evolutionary more distant from humans are less likely to share mechanisms of aging that are relevant in humans.
One crucial aspect of research on aging, which is sometimes overlooked by researchers, including myself, is that our work should deal with human aging. Aging in model organisms is irrelevant if it is not applicable to humans. Some mechanisms of aging identified in model organisms may be relevant to human aging while others may not, but discriminating between the two is often impossible, as argued elsewhere. As such, it is imperative we keep a skeptical mind when analysing data from model organisms, particularly non-mammalian models (de Magalhaes and Toussaint, 2002 & 2004b).
Once we know more about which mechanisms to target, we can consider the development of therapies (Fig. 2). It is somewhat speculative to consider anti-aging therapies at present, since we know little about what interventions will be necessary, but a few ideas are given below and elsewhere. I am optimistic, however, that as researchers address the two questions mentioned above, we will eventually develop true anti-aging therapies.
Figure 2: Steps necessary to gain enough information about aging to start considering a cure: identify therapeutic targets by studying why we become frailer with age and/or why we age slower than most other mammals; develop technologies capable of targeting the molecules, cells, or tissues necessary to revert aging, as detailed ahead.
Strategies for Engineered Negligible Senescence: A Critique
Strategies for Engineered Negligible Senescence or SENS is a proposal by Aubrey de Grey to cure aging (de Grey et al., 2002; de Grey, 2003; also visit the official website). Briefly, his proposal is that even if we do not know the underlying mechanisms of aging, if we can engineer the reversal of all the major molecular and cellular changes that occur with age, we will be able to achieve rejuvenation. The proposal includes addressing seven forms of molecular or cellular damage that accumulate with age, which were chosen based on earlier works (Holliday, 1995). Reversing these changes, however, will require technologies, or at least therapies, that are not yet available. These include stem cells to replace old cells, the application of enzymes--including bacterial enzymes--to degrade certain forms of "cellular junk," gene expression technologies that allow the incorporation of transgenes with a high efficiency and viability, and the ablation of old cells.
The idea that curing aging may be possible even before we can fully answer the two main issues discussed above (Fig. 2) is original but controversial. Actually, de Grey assumes we can answer question 2) to some degree: that we can understand the changes that occur with age well enough to develop therapies, even if the causality of these is not established. Like previously discussed, many pharmaceutical interventions work as intended even though we do not know why. Some anti-aging therapies may follow the same principle: for instance, maybe we do not need to know the exact functions of klotho to develop anti-aging therapies, as discussed earlier. SENS, however, promises radical results: a cure for aging. The idea that we can cure a complex process like aging without knowing its underlying mechanisms is, of course, debatable, even though it is plausible that if the technologies in which SENS is based on--e.g., stem cells, tissue engineering, and gene therapy--reach a high level of efficiency then anti-aging research will greatly benefit. Even so, that does not offer any guarantee that we will be able to cure aging.
The main criticism of SENS comes from analogies with other medical problems like cancer and AIDS. From a engineer's perspective, both cancer and AIDS are simple problems: all we need to do to cure these diseases is the ablation of cancer cells or, in the case of AIDS, HIV. This is similar to the ablation of old cells in the SENS proposal. In the case of SENS, de Grey proposes that ablation of cells may be achieved by making unwanted cells commit suicide or stimulating the immune system to kill them. The problem is: if the ablation of unwanted cells were so simple, then why have decades of cancer research, with more money than that available to aging research, failed to do so? Again, it can be argued that we still do not have the necessary technologies but now are on the verge of having them. One the other hand, critics of SENS point out that perhaps these engineering achievements are not as easy as they may seem at first due to intrinsic problems of biomedical research, such as its unpredictability. Overall, critics of SENS argue that all individual components of the SENS proposal are highly optimistic, though these same critics often reject any possibility to prevent aging indefinitely or reverse aging (Warner et al., 2005), which in view of the unforeseen progress of recent centuries I would consider as highly pessimistic.
August Weismann wrote: "The complex processes of life can only be followed by degrees, and we can only hope to solve the great problem by attacking it from all sides." I believe that in a field like gerontology where proven facts are rare, it is important to invest a certain amount of resources in unorthodox practical research; reasonable ideas that go against some of the most popular theories can also be successful and History proves it. When Einstein thought and developed his ideas trying to solve the paradoxes relating light speed and confronting Newton's and Maxwell's laws, he was unaware that others were thinking about the same problems; this was a blessing, for the others were heading in the wrong direction and could have clouded his thoughts. While many in the field of aging doubt SENS, and I too see scientific problems in this approach, I still wish that de Grey has a chance to prove his ideas as maybe something positive will come out of it.
The Importance of the Brain in Anti-Aging Research
Theoretically, the only organ that cannot be replaced is the brain. In practice, lifespan is equivalent to brainspan. Following an earlier discussion, it is open to debate whether aging is caused by factors that do not have their origin in the brain. Perhaps our brain just ages because the other organs in the body can no longer support it (but see below). If we could change the body at regular intervals to keep it always young, it might happen that our brain would never age. Technically, we might soon be able to transplant entire bodies. Robert White has already experimented body transplants in animals: separating the head from the body and then insert the head in a new body (White et al., 1996). (Notice the fact that I call it "body transplants" and not "brain" or "head transplants" because size does not matter here; the brain is us, and can never be changed, but the body can, and therefore it is the body that is transplanted.) Of course, body transplants, even if they are made to work, are a difficult and expensive technique.
It is also possible, though speculative, that future developments in cybernetics and therapeutic cloning will make it possible to replace all other organs. But even if we could replace the most vital organs with either new or artificial organs, it appears to be a difficult, dangerous, and unpredictable approach. Also, many theories center aging on post-mitotic tissues such as neurons, so the idea that we could avoid brain aging by replacing or rejuvenating the rest of the body is likely incorrect. Perhaps it is worth to try in animals as we might learn something out of it. For now, we must focus on trying to discover a way to stop aging in all the body, having, of course, the brain as top priority.
Short-term memory loss, personality and cognitive changes with age, dementia, general decline of the nervous system and senses, and many other changes are likely to occur with aging (Craik and Salthouse, 1992; Hayflick, 1994, pp. 161-166; Zec, 1995). Until recently, it was thought that neuronal loss, due to the accumulation of damage--such as oxidative damage--was the main cause of brain aging. Nowadays, it appears that neurons can remain relatively healthy through life, with the exception of pathologies (Morrison and Hof, 1997). In fact, until recently, neurons were not thought to be able to divide. Now it appears that neurons can replicate in adult monkeys, in an area of the brain called hippocampus, which is used for long-term memory (Gould et al., 1999). Similar results have been reported in humans (Eriksson et al., 1998). (Altman and Das, 1965), and Fernando Nottebohm reported brain rejuvenation in birds (Nottebohm, 1989).) Instead of seeing brain aging as a mere consequence of the death of neurons, it appears that, even without neuronal death, biochemical and structural changes compromise neuron function (Teter and Finch, 2004). With age, what changes is the wiring, the complex network of connections between cells (Gopnik et al., 2000). It has even been suggested that brain aging is an extension of brain development (de Magalhaes and Sandberg, 2005), in line with a linkage between development and aging. While the jury is still out, the debate of whether aging is a result of damage accumulation or of programmed events also extends to brain aging.
Fighting Aging: The Road Ahead
"By the year 2030, we will have (1) developed a complete model of all human cell types, obviating the need for many laboratory experiments [by doing computer simulations instead]; (2) lowered the cost of doing a complete genomic sequence for an human individual to less than $1,000 each; and (3) catalogued all the genes involved in aging. Therefore, human clinical trials to extend lifespan could already be underway by this date."Francis Collins
Studies done in silico will be one of the major sources for determining what causes aging. I remember an e-mail I got from a young immortalist who was studying computer science because he thinks that the key to solving human aging is in computers and artificial intelligence and not in biology--i.e., by building computers smarter than us capable of solving the problems we can't solve. I do not share his enthusiasm, but I agree that solving aging will be partly based on computational biology (de Magalhaes and Toussaint, 2004b).
Figure 3: If we can understand the genetic factors that determine the rate of aging among similar species, like primates and rodents, then it may be possible to develop interventions that extend the human lifespan even further. Figure rendered using the animal fonts by Alan Carr.
In a sense, the human genome has everything we need to know about aging and we may have the secret of immortality in the genomes of animals that appear not to age; the problem is that the secret is encrypted and it will take a great deal of work and processing power to understand it. Computers will play a major role in deciphering that secret and determining the mathematics that might be behind the secret of immortality. Of course that there are difficulties. The genomes of many viruses have been sequenced years ago and we still cannot cure the diseases associated with them, as discussed ahead. Besides, the genetic differences that determine rate of aging are likely very subtle. For instance, humans and chimpanzees have about the same set of genes. It is thought that subtle differences in proteins or in transcriptional regions determine the differences between chimpanzees and humans (Carroll, 2003; Olson and Varki, 2003). Consequently, subtle genetic differences are also expected to determine rate of aging, and finding these in the billions of base pairs that make up a genome will be a Herculean task (de Magalhaes, 2003; de Magalhaes and Toussaint, 2004b). Eventually, however, the genome holds all answers, all we need to do is ask the right questions (Fig. 3).
"I'll live forever or die trying."anonymous
While I think that there are genetic factors that make up a unifying core of human aging, it is impossible to say how many genes are involved; besides, it is possible that some age-related changes are independent of this fundamental core. Maybe some age-related pathologies are the result of single late-acting genes. In fact, if late-acting deleterious genes do exist, then it is possible that there are deleterious genes affecting species after the maximum lifespan of species--say, after 300 years in the case of humans. These could result in a disease or even in some form of mechanical senescence. I call these genes whose effects are deleterious after our present maximum lifespan post-mortem lethal genes (Magalhaes, 1999). Take as an example the diseases that result from the levels of a given defective protein passing a certain threshold, like mad cow disease or familial amyloidotic polyneuropathy, which can be the result of a long-term accumulation of the defective protein of a slow-acting infectious agent. Maybe if we increase our maximum lifespan we will also increase the number of people affected by this kind of diseases.
Overall, determining the genetic basis of aging will be a monumental task. Still, I feel confident that we will be able to identify all the genetic mechanisms that cause aging within my own lifespan by the combination of approaches mentioned earlier (Fig. 1). Yet even if we do, we will still have to order our cells not to age. How to do this is the subject of my next essay.
"We, alone on earth, can revolt against the selfish replicators"Richard Dawkins
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