I plan to live forever, you?

posted in: Aging | 0

When I was a child, I had this persistent belief that I will live forever. Recently, I have been wondering if living forever is indeed a tangible thing or science fiction. To understand and think about ways of delaying or stopping ageing altogether, we need a solid definition of what constitutes ageing first. Without having claims of being an expert in the field, I am going to try and present a comprehensive definition of the process and discuss some interesting directions in the field.

One of the most concise definitions of ageing I have come across is that by Comfort (1964): “age-related loss of viability and increase in vulnerability”. This definition, however, fits equally well a car, a piece of clothing or a living being. Since I am going to focus on biological ageing, I will use Dr. Aubrey de Grey’s definition of the process because of its all-inclusiveness and, at the same time, specificity: “Metabolism ongoingly causes damage. Damage eventually causes pathology.” De Grey postulates the existence of a damage accumulation threshold, above which complications lead to eventual death. He gives a summary of age-related pathologies whose prevention or treatment is the target of age-related research.

1. Chromosomal mutations with the potential to cause cancer
2. Glycation or non-enzymatic glycosilation
3. Accumulation of extracellular junk (ex: beta-amyloid)
4. Accumulation of intracellular junk (ex: lipofuscin)
5. Cellular senescence and cellular toxicity
6. Depletion of stem cells
7. Mitochondrial damage related to increased oxidative stress

All of the big ageing research breakthroughs address at least one of the above-listed pathologies. For example, Jaskelioff et al. (2011) managed to counteract replicative senescence and to rejuvenate mice with shortened telomeres by reactivating telomerase. This resulted in longer telomeres, less DNA damage signalling, re-establishment of proliferation in quiescent cells. Furthermore, the procedure reversed degeneration in testes, spleen, intestines and neural tissue. The authors observed no carcinogenesis for the period of telomerase reactivation they used in the study. They do, however, acknowledge the possibility that a prolonged telomerase reactivation period, in combination with the already unstable genome of telomerase-deficient mice, might eventually result in tumour formations (Jaskelioff et al., 2011).

Another example is the very influential wave of calorie restriction studies. Calorie restriction was found to contribute to extended lifespan and a delayed onset of age-related diseases in a wide variety of organisms – yeast, worms, flies, mice, etc. (Heilbronn and Ravussin, 2003). Since calorie restriction is associated with profound changes in metabolism, it is difficult to disentangle the sole cause of life extension. Hypotheses vary, but among the most predominant ones are those suggesting that calorie restriction attenuates the production of reactive oxygen species (ROS), increases cellular oxidative stress resistance and inhibits inflammatory pathways (Ungvari et al., 2008).

Apart from not having certainty regarding the cause of starvation-induced life extension, it is worth pointing out that starvation studies have not all been a ravishing success. One example is Mattison et al. (2012) who failed to replicate previous findings using rhesus monkeys as subjects.
A very fruitful line of ageing research is related to the genetic condition progeria. People with the condition start showing signs of normal ageing while they are still in their childhood and rarely live to 20 years of age. Liu et al. (2005) demonstrated that lamin A, an important building block of nuclear lamina and skeleton, is a strong candidate for being the causing agent of progeria. A truncation of lamin A and absence of a functional Zmpste24 (responsible for the maturation of lamin A) act in a dominant negative fashion to prevent normal DNA damage response from taking place, thus leading to inefficient damage repair and genomic instability (Liu et al., 2005). Hence, the threshold of pathological damage accumulation that de Grey talks about is crossed much earlier than in a healthy organism. One criticism related to interpreting results from progeria studies is that we do not know with absolute certainty if progeria is simply sped-up ageing. In fact, the overlap between genes found to influence lifespan in model organisms and those found in progeria studies is not very impressive (Burtner and Kennedy, 2010).

Although the progress that has been made in recent years in ageing research is immense, it might be worth stepping back and looking for new sources of inspiration. Most studies target only one of the known causes of ageing. Hence, their conclusions do not paint a complete picture. Also, the majority of ageing research’ findings have been made using well-studied model organisms. These organisms were chosen because of scientists’ familiarity with the organisms’ genetics and not because of their unique suitability for answering ageing-related questions. An idea worth exploring might be to look at animals that have faired particularly well in evolving to have a long lifespan. One such choice is the bat. Two defining characteristics of the bat are that it is the only mammal that can fly and that it is a virus hoarder. It also has a remarkably long life compared to other mammals its size, like rats for example (Zhang et al., 2012). Zhang et al. (2012) sequenced the genomes of 2 different bat species and performed a comparative study between them and other animals’ genomes. Positive selection for the oxidative phosphorylation pathway (OXPHOS) in bats argues in favour of the presence of increased metabolic capacity, which is necessary for developing the ability to fly. However, a method of coping with the byproducts of oxidative metabolism (ex: ROS) would also be required. This requirement is fulfilled, as demonstrated by the rapid evolution of the genome of the bat’s mitochondria and positive selection for genes in the DNA damage/repair pathway (Zhang et al., 2012). Another interesting finding was the positive selection in the bat’s ancestor for c-REL, a member of the NF-κB family. C-REL is involved in both immunity and DNA damage response. The authors argue that changes in the bat’s DNA damage pathway and immune system might be reflective of flight-induced evolutionary changes having a collateral effect on the animal’s immune function and lifespan. Hence, bats might turn out to be important for gaining new insights into ageing and immunity. The modifications in their mitochondrial genome could be one lead worth pursuing. In an interview, de Grey points out the fact that only mitochondrial damage out of the seven age-related pathologies is not associated with a concrete disease. He suggests that could be for two reasons – either because it has negligible contribution to ageing or because its effects are much more pervasive than we realise.

Having started this piece with Aubrey de Grey’s ideas and definitions, I would also like to also finish with them. Observing the progress of ageing research in recent years, a tiny fraction of which I have presented here, I cannot help but think of what de Grey calls ‘Longevity Escape Velocity’. This is the idea that if one is middle-aged (i.e. no serious life-threatening conditions have occurred yet) at the time of the development of the first generation of life-extending drugs, one could extend their healthy life with a certain amount of years. During those newly gained years, the second generation of drugs might appear on the market and lead to more healthy years being acquired by the individual. In theory, this cycle could go on indefinitely and a young person living at this very moment could in this way potentially become immortal or at least extend their life in proportions unconceivable from today’s perspective. Therefore, the prospect of immortality should start being perceived as more than just science fiction.

References:
Burtner CR and Kennedy BK (2010). Progeria syndromes and ageing: what is the connection? Nat Rev Mol Cell Biol., 11.
Comfort A (1964). Ageing. The biology of senescence. Holt, Rinehart & Winston: New York.
de Grey ADNJ (2004). Escape Velocity: Why the Prospect of Extreme Human Life Extension Matters Now. PLoS Biology, 2(6).
de Grey AD and Rae M (2007). Ending Aging, St. Martin’s Press.
Heilbronn, LK and Ravussin, E (2003). Calorie restriction and aging: review of the literature and implications for studies in humans. Am. J. Clin. Nutr., 78.
Jaskelioff M et al. (2011). Telomerase reactivation reverses tissue degeneration in aged telomerase-deficient mice. Nature, 469.
Liu B et al. (2005). Genomic instability in laminopathy-based premature aging. Nature Medicine, 11(7).
Mattison J (2005). Age-related decline in caloric intake and motivation for food in rhesus monkeys. Neurobiol Aging, 26.
Ungvari Z et al. (2008). Mechanisms underlying caloric restriction and lifespan regulation: implications for vascular aging. Circ Res., 102.
Zhang G et al. (2012). Comparative analysis of bat genomes provides insight into the evolution of flight and immunity. Science.