The dream of immortality may have been the oldest desire of human kind. The Epic of Gilgamesh, one of the first literary works, dating back at least to the 22nd century BC, is a quest of a hero seeking immortality (tablet XI, Utnapishtim). Since the earliest times we are neither able to accept nor imagine the end of our existence. Because of this inability, the alternative explanation of mortality has become an integral part of the dogma of most, if not all, religions. Among others, the Christians' promise that being devoted will grant you post mortal life in heaven, or the presumed ability of advanced Yogis to extend lifespan by spiritual-jump into another human body, or as in Buddhism or Hinduism by migration of your spirit into another species after death. The thousands years of struggle to avoid mortality were from a religious perspective successful. In now a day society, religious social structures and sects give a direct answer to this question. However not for all, even religious people, such an answer is acceptable. Here I would like to share the theories that dominate gerontology today and are relevant to either explaining or preventing aging.
1. What is aging?
It is well accepted today that aging is a stochastic process of accumulation of damage over time. The damage starts on molecular level and accumulation of damage leads to malfunction on cellular level. DNA modifications are believed to be at the beginning of the chain of events that constitute aging process. DNA damage eventually leads to differential protein expression or erroneous protein folding and binding. Once protein damage has accumulated the cell starts to malfunction. Malfunctioning cells either suicide (apoptosis), enter the state of reduced, but often harmful activity (cellular senescence), or develop into neoplasia (abnormal proliferation such as cancer). During lifespan all three processes actively reshape our organism and lead to aging and ultimately death.
2. Aging is not a prerequisite of life
There are many misconceptions about possibility to increase lifespan. Most misconceptions can be categorized either under the ethical perspective or biological plausibility. Since the ethical perspective such as overpopulation, accumulation of wealth, end of the evolution are well covered by philosophers, radical thinkers [1], and sociologists, here I will only comment on biological plausibility. The main argument in favor of lifespan extension is the evidence from nature, i.a. evidence from other organisms. Many organisms are considered to have neglectable senescence and many more have lifespan much longer than ours, and therefore maintain themselves better. The aging process has evolved markedly different between species. Some species, such as Hydra under stable conditions escape aging. Others, long lived invertebrate species, such as the bivalve mollusk ocean quahog maintain themselves so good that they have been estimated to live up to 400 years [2]. Pedro de Magalhaes describes these and other examples in more detail on his web site.
3. Aging theories relevant today
The scientific theories of aging that are discussed now a day are: programmed, antagonistic pleiotropy and disposable soma theories. All three go well with P. B. Medawar mutation accumulation theory [3]. Group selection explanation for limited lifespan, which I find very interesting is not considered mainstream gerontology [4]. There is no unified theory of aging, however all the above mentioned theories contribute and otherwise partly explain the aging process. I will mention the most important aspects of mainstream theories as logical consequences of selection shadow mechanism[3] while intentionally omitting some conflicting interpretation of these theories.
3.1 Selection shadow
Selection shadow was coined by P. B. Medawar in 1952 [3]. The reasoning of P. B. Medawar is that once the animal is no longer able to contribute to the next generation, his role in the selection process is lost. Such an animal enters a grey area called “selection shadow” where his destiny is not shaped by evolutionary selection.
Medawar explained selection shadow mechanism on the example of non-living objects. Here is another example, an example of lifespan of a car motor. The manufacturer is often required to cover the first three years of lifespan of the motor. The manufacturer, playing the role of the natural selection, develops the technology and materials that assure that the motor survives at least for the first three years. After initial first three years, the manufacturer does not benefit from motor reliability and the motor enters the grey area of selection shadow. During the selection shadow, the technology developed to maintain it for three years may still be working. However, if the motor works only for three years and wears off immediately after, it does not influence the manufacturer income (at least directly). The living organism follows similar rules, but in the world of DNA each and every feature (gene) undergoes constant testing for usefulness. Natural mutation rate makes sure that genes get randomly mutated, shifted, extended or reduced (polymorphisms) and recombined generation after generation. These processes are the ones that allow us to adapt to the changing environment. If the polymorphism is beneficial for environment then it is selected to prevail in upcoming generations. However any other non-beneficial polymorphisms also stay within the germline evolution. As long as new polymorphisms do not damage the organism before the onset of selection shadow there is no selection pressure applied to them. Even if an organism is potentially immortal, given time and enough generations, all the genes that are required to maintain the organism outside the selection shadow will undergo change and their function will wear off. In any immortal organism, the initial immortality will inevitably wear off in his descendants so to match the selection shadow onset. We, human, are not an exception and we are genetically selected to survive till the onset of selection shadow. Since selection shadow is under strict genetic control, we enter the realm of another aging theory - Programmed Theory of Aging (PTA).
3.2 Programmed Theory of Aging
PTA states that our lifespan is determined genetically. The main argument in favor of PTA is that lifespan of organisms in one species can be significantly different from another species (e.g. mice and human). Therefore lifespan limit is hereditary within the species. Since it is hereditary it is most likely transmitted through DNA replication mechanism. Humans' maximum lifespan is 122 years, mice's 4 years, bowhead whale's 200 years, and under favorable conditions hydra lives so long that it's lifespan is hard to determine experimentally. There is little doubt that in this species different lifespan limits are transmitted from one generation to another, and that these limits are controlled genetically when compared among species.
As mentioned in section 3.1, natural mutation rate mechanism has a negative effect on lifespan during selection shadow period. Selection shadow reasoning leads to understanding that there is no single biological machinery that is responsible for control of lifespan, but rather machinery that is designed to function until the onset of selection shadow. In a motor evolution, a better designed component that fills the customer needs can replace an old one as long as they make the whole system better suited for the environment. The recent appearance of high revolution motors that are more economical but wear off faster and the increasing use of less durable (and less expensive) materials in motor manufacturing process illustrate well the ongoing trade-offs in motor evolution.
The biggest critique of any research relying on PTA, is that improving any specific machinery alone will not extend lifespan indefinitely. That is if we replace one part of the motor the motor won't live forever as a consequence. Most cellular mechanisms, if not all, are designed to function only as long as required by the environment. So to indefinitely extend lifespan you have to address all the mechanisms that wear off. As long as this reasoning is considered, the programming theory of aging makes sense and should be taken seriously (inferred from the discussion with Rudi Westendorp). However, improvements to one particular machinery do offer limited lifespan extension [5, 6] and such human made improvements do not contradict selection shadow reasoning. Free Radical Theory of Aging describes some of the molecular mechanisms of aging [7-10]. Telomere Shortening Theory of Aging describes another mechanism [5, 11]. Even lifespan extension through dietary restriction can be interpreted as PTA (maintenance switch). In spite of often overestimating the effect of those techniques, today those behind these theories are the driving force of active lifespan extension.
3.3 Disposable Soma Theory
Half a century after P. B. Medawar, T. Kirkwood revived selection shadow reasoning and argued that animals in selection shadow are disposable [Evolution of ageing. 1977], hence the name “disposable soma theory”. Disposable soma theory (DST) assumes that the energy available to the organism is limited. T. Kirkwood explains that there is always a balance in how much energy an organism can afford spending on staying healthy and on how much to invest on sexual reproduction. If we accept this assumptions, the theory is logical. However, success of some of PTA projects contradict DST. DST is a very interesting observation that has proven valid in many cases in natural environment. Unarguably DST contributes to understanding of aging, but is not directly helpful in research oriented to lifespan extension .
3.4 Antogonistic Pleiotropy
Antogonistic pleiotropy (AP) is yet another theory that intends to explain selection trade offs that influence aging. AP can also be explained using motor example. If manufacturer develops techniques that are beneficial to a motor during warranty period, in spite of being detrimental on a longer run these techniques can be eventually incorporated into new generations. We can see such selection tendencies in now a day motors with appearance of high RPM motors. Most high RPM motors wear off faster than normal motors. However this motors offer higher performance for less development and operational costs. This trend of preferring high RPM motors illustrates the trade off between short term advantage of higher efficiency that leads to shorter lifespan. Therefore G.C. Williams in 1957 [12] called this trade off Antogonistic (opposing) Pleiotropy (more than one effect), referring to that genes (features) that benefit an organism before the selection shadow can be detrimental in later life. There are striking similarities of AP and PTA, however I expect that some of the scientists looking for AP genes will strongly oppose this view.
3.5 Other theories explaining aging
Other, theories I cannot omit are:
· Grandmother effect. An indirect mechanism of selection that works postponing the selection shadow. Long-living after menopause did not directly influence the life and reproduction efficiency of a certain person or species, but still increased the fitness of species over a generation (of grandchildren) [12]
· Male driven longevity. Extended human longevity effect explained by D. Boudegom et al [13] referring to our recent polygamous past. Since man in polygamous societies tend to marry and have children later than in monogamous societies, than there is likely man-driven selection on longevity.
4 Efforts to fight aging
A careful reader seeking an answer on how to fight aging would have noticed that the aging theories described in section 3, provide an explanation of the mechanisms of aging, and by no means describe how to fight aging (with the exception of Programmed Theory of Aging). Explaining the tradeoffs and their limitations is crucial for understanding the aging process, but does not tell how to extend lifespan. Moreover, other direct interpretations of the DST and AP argue against the possibility of life extension. Never the less, there are countless publications that describe genetic modifications on model organisms that contradict DSP and AP by extending lifespan. Additionally, two projects that set extending lifespan as their direct goal are mentioned below.
4.1 SENS
One of the reasons behind my decision to study aging was Aubrey de Grey and his projects described in Strategies for Engineered Negligible Senescence (SENS). SENS is a set of projects, each describing a flaw in human biology that leads to senescence together with solutions to these flaws [14]. I find some of the projects and ideas of SENS hard to achieve and some of them outright unrealistic. In spite of that, Aubrey de Grey is one of the few who were able to identify and summarize processes that presumably lead to aging and, most importantly, may be the first one to offer a viable solution at least in certain areas. SENS projects include:
· OncoSENS – A strategy to fight cancer by inhibiting telomere extension. Very much criticized due to the fact that this strategy eventually shuts down all cell proliferation.
· LysoSENS –A strategy to incorporate bacterial enzyme into human genome to enhance lysosome digestion abilities.
· AmyloSENS – A strategy to eliminate cross-linked proteins in extracellular matrix.
· RepleniSENS – A strategy to use stem cell therapy, regenerative medicine and tissue engineering to replenish a loss of cells due to aging.
· ApoptoSENS – A strategy to eliminate senescent cells
· GlycoSENS – A strategy to eliminate glycation cross links among cells
4.2 2045.ru
2045.ru is a recent Russian initiative that focuses on building a synthetic humanoid body capable of replacing the human body. In principle very ambitious, interdisciplinary and goal oriented project. The project, or rather a movement, is supported by many celebrities, among them scientists. Unfortunately, this project still does not have international community fully involved. Never the less, 2045.ru is one of the few projects that has life extension as a clear goal together with a clear plan on how to achieve it (http://2045.ru).
5 How to achieve life extension?
Following the reasoning of Aubrey de Gray and the founders of 2045.ru along with hundreds of other scientists it is clear that eventually indefinite life extension will be achieved. However it is important to understand that life extension cannot be achieved on short term by genetic modifications alone. We are neither designed to live forever nor do we have unique genetic mechanism that controls our lifespan. We will eventually be able to modify our genetic code so that our cells do not suffer from the flaws they are suffering right now, but the pace with which we learn to modify our genome make this goal unlikely to succeed in near future, at least by means of genetic modifications and drugs alone. However, it is not necessary to fix all processes involved in aging to indefinitely extend lifespan. Considerable (potentially indefinite) life extension can be developed by radical changes in diagnostics and treatment.
5.1 Diagnostics and treatment of tissues on cellular level
Aging on molecular level leads to aging on tissue level. For example skin. With aging, the epidermis (outer skin layer) becomes thinner [15]. The number of melanocytes (pigment containing cells) decreases and the remaining melanocytes increase in size. Changes in the connective tissue reduce the skin's strength and elasticity. Sebaceous glands produce less oil as you age. The subcutaneous fat layer becomes thinner, reducing insulation and padding. The sweat glands are less productive and therefore increase risk of overheating and a risk of developing heat stroke. All of the above changes are just a small part of the aging-induced processes that affect a small par of human body, skin. Most of other 200 tissues in our body also undergo similar number of age-related changes. While it is unlikely that we soon going to be able to reverse aging induced processes on molecular (e.g. DNA) level, it is quite probable that tissue engineering is able to fix some of the issues on shorter term basis. Tissue engineering is at the state where cells from an individual can be grown in vitro, made pluripotent without becoming cancerous and be differentiated (to become tissue specific) [16]. Integration of these cells into tissues is subject of public attention, hopefully successful enough to become available within a few years. These therapies and techniques are numerous and all of them can aid diagnostic and treatment on cellular level. Example of one of the techniques is the use of nanowires for drug delivery [17]. In the experiment by T. Fan et al. the authors manipulate microscopic gold particles in the magnetic field and delivers them into the cell membrane of a target cell. Once automated, such technology is capable of tissue renewal. However new technologies that could aid tissue engineering (diagnostics and treatment) emerge almost on per year bases:· gold nano-particles [18]
· 3d bio-printers[19]
· the increase of MRI resolution with MRFM [20]
· reduced costs of MRI through Prepolarized MRI[21]
· next generation sequencing [22]
5.2 Cancer
Cancer and aging are becoming tangled processes. For instance, mice's "natural" death in laboratory environment is always caused by cancer. Alike mice, human are increasingly successful in eliminating other environmental hazards and therefor cancer is becoming the number one cause of death in modern societies. Biologically, cancer is a consequence of unregulated cell division. Among other prerequisites for cancer is cell cycle arrest. Cancer can only develop after an accumulation of multiple somatic mutations in pathways that regulate cell cycle. Consequently cell loses apoptosis mechanism. As the result, the mutation rate in it's progenitors increases to the extend where mutation accumulate so fast that these changes become difficult to control on molecular level through interacting molecules [23]. In spite of a number of advances in the area of cancer research [24], targeting specific mutations is very difficult and most often restricted to only certain types of cancers. The fact that development of specific compounds is required for a number of frequent mutations has attracted many pharmaceutical companies. However such a research, in spite of being well funded, will not “cure” cancer, only improve treatment for most common cases of cancer and delay the onset of aging. This aging limit is the reason why gerontologists often discuss cancer. Due to its stochastic nature cancer is becoming the leading cause of death in economically developed countries. In most fist world countries, in spite of advances in healthcare treatments, cancer prevalence increases each year. Today cancer prevalence has reached approximately 30.1% for man and 22.0% for woman becoming the first most probable cause of death [25]. No one is safe and even the longest lived are susceptible to cancer [26, 27]. However some promising technologies address cancer from different perspective.· Immunotherapy [28, 29]. Isolation of immune cells, enriching them outside the body and transfusing them back to the patient, consequently making immune system react against cancer as it would react against viruses or foreign organisms.
· Development of technologies of focused point radiation to treat cancer [30]. Treating the tumor with radiation is usually effective, less risky than surgery, and the vast majority of tumors do not grow back.
· Vaccination to prevent virus infection [31]. Some vaccines result in lowering cancer risks.
6. Conclusion
Given enough interest, considerable lifespan extension can and most likely will be achieved. However, due to complexity of biological processes, lifespan extension is not going to be achieved through genetics alone, but rather through development of better diagnostics techniques and cooperation of genetic and tissue engineering fields. The greatest limiting factor in lifespan extension today is cancer. The most effective way to deal with cancer is to prevent it. Given my academic formation, I will continue this writing exercise and focus my academic efforts to promote some innovative ideas in cancer prevention.
7. References
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