Mitochondrial genome anatomy and species-specific lifespan

The reasons for some animals being long-lived and others short-lived, and, in a word, causes of the length and brevity of life call for investigation.

— Aristotle, On Longevity and Shortness of Life (350 B.C.)

Humans and animals have two different DNAs: (1) nuclear DNA and (2) mitochondrial DNA (mtDNA). The nuclear DNA resides is in the cell nucleus and the mtDNA resides in the cell mitochondria. The consequence of the different localization is that the metabolic environment as well as the repertoire of proteins is different. This includes the DNA repair and maintenance machineries.

Over the last decade, a particular phenomenon was observed which suggests that the mtDNA is the important determinant of animals maximum lifespan (MLS). This evidence is that the chemical composition of the mtDNA (and not the nuclear DNA) correlates with animals characteristic maximum lifespan (MLS; figure 1) [1,2,3,4]. The mtDNA chemical composition is actually its base composition (A, T, G, and C) and therefore it is quantitatively measurable. Figure 1 presents the correlation between the mtDNA GC-content and maximum life span across 387 different species of mammals.

Figure 1. Unbelievable correlation between the mtDNA GC% and mammalian species lifespan.

The correlation between the mtDNA GC and MLS (Figure 1) is considered strong in the field of biology where extremely complex systems are studied. Further strengthening the confidence in the link between the mtDNA and MLS is that another feature of the mtDNA correlates with MLS - its size [5]. Besides the mtDNA GC, another factor is known to correlate with animals MLS - resting metabolic rate (RMR)[6,7,8,9,10,11]. RMR is an approximation to the minimal energy expenditure of animals and is measured at a condition of rest. It therefore represents the low threshold of energy usage just to stay alive. The RMR correlates tightly with MLS but it does not correlate with the mtDNA base composition [2]. Furtheremore, the RMR and the mtDNA base composition explain different parts of the variability in animals MLS [2,3,5]. As follows, the mtDNA and RMR can be used as two independent predictors of MLS (from statistical perspective). The practical implementation of this notion is illustrated in figure 2 where the combination of mtDNA and RMR explains 3/4 of the MLS differences among mammals. In other words, the combination of mtDNA and RMR allows to generate the strongest correlations with MLS that have been reported to date (for comparable sample size of animals, i.e., not just 3 species). The mathematical function for the dependence of MLS on mtDNA and the RMR is multiplicative (MLS = e^mtDNA * RMR, or; logMLS = mtDNA + logRMR) and suggests that although the mtDNA and RMR are independent (statistically), they do interact in determination of MLS.

Figure 2. Combined, the mtDNA GC% and RMR explains ~75% of the variation in mammals longevity.

It is a matter for debate why the mtDNA base composition and RMR correlate with MLS, and why they seem to be statistically independent from each other. A possible explanation is that the mtDNA represents the pathway for energy production by the mitochondria while the RMR represents the cellular pathways for energy comsumption. The energy production and energy consumption pathways are independent from each other but could interact in determination of MLS. Thus, the mtDNA GC and RMR are two sides of a same coin. On one side of the coin, the mtDNA base composition reflects a capability to protect the mtDNA and preserve the ability to generate energy from food and on the other side, the RMR represents an ability to contain a decrease in the mitochondrial energy generation. For illustration, a mouse with high RMR is susceptible to decline in its mitochondrial ability to generate energy while turtles and elephants with very low RMR are can endure such decline for longer time (and thus live longer).

Alternative explanations for the mtDNA and RMR correlation with MLS are that they are both mediated by radical oxygen species (ROS). Higher metabolic rate is associated with higher ROS production rate, and changes in the mtDNA base composition are associate with change in the mitochondrial proteins that produce ROS, presumably leading to less ROS production by the mitochondria [12,13,14,15,16]. Another alternative is that the amino acids changes alter the stability and vulnerability of the mtDNA coded proteins which are important for longevity [16,17]. Specifically, it has been suggested that accumulation of threonines and serines in the mtDNA encoded proteins is advantegous for longevity [18,19], that less cystein is advantageous for longevity [20], and that less methionine is advantageous [21]

It is not clear how to successfuly translate the findings on the mtDNA-MLS links into action items. The SENS Research Foundation has set as a goal to make backup copies of the mtDNA genes in the nuclear DNA (a process called allotopic expression). Copies of mtDNA chunks already exist in the nuclear DNA and they are called NUMTs (for nuclear mitochondrial segment). As far as we know, these NUMTs are not functional because the mtDNA and nuclear DNA have different genetic codes, including different stop codons. In one lizard however, that is named Sphenodon punctatus (tuatara), the mtDNA lacks the genes ND5, tRNA(His) and tRNA(Thr) which are suggested to have moved to the nucleus [22]. According to the records in the AnAge database, the tuatara lizard weights less than 1 kg and can live 90 years and probably more [23]. This supports the potential direction of lifespan prolongation by allotopic expression. Another potential action item could involved the study of mitochondrial transfer between cells [24], a process that can rescue cells with defective aerobic respiration [25,26,27,28,29]. A yet different possibility is to study the ability of young people stem cells to rejuvenate old people. More possibilites exist.

To accelerate the research on the link between the mtDNA and MLS and to demonstrate the reliability the data, the MitoAge database was constructed [30]. MitoAge contains calculated mtDNA compositional features of the entire mitochondrial genome, mtDNA coding (tRNA, rRNA, protein-coding genes) and non-coding (D-loop, insertions) regions, codon usage for each protein-coding gene, and longevity records for over 900 species from all taxa of the Kingdom Animalia. By downloading the data from MitoAge, anyone can in short time reproduce figure 1 and beyound, and observe the correlative links between the mtDNA and MLS.

Below are presentations that I gave about this research in two conferences.

Presentation 1. Mitochondrial determinants of mammalian longevity. Understanding Aging: Biomedical and Bioengineering Approaches, UCLA, Los Angeles, CA, June 28-29, 2008.

Presentation 2. Mitochondrial Determinants of the Mammalian Life Span. Eurosymposium on Healthy Ageing. A new age of long term health and longevity. Brussels, December 12-14, 2012.

References

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