Age changes can occur in only two fundamental ways: by a purposeful program driven by genes or by random, accidental events.
It is a cornerstone of modern biology that a purposeful genetic program drives all biological processes that occur from the beginning of life to reproductive maturation. However, once reproductive maturation is reached, thought is divided with respect to whether the emerging aging process is a continuation of the genetic program or whether it is the result of the accumulation of random, irreparable losses in molecular fidelity.
The deterministic dream of 19th century physicists was torpedoed in the 20th century with Heisenberg's discovery of the uncertainty principle. In fact, the fundamental laws of physics can only be expressed as probabilities. The most compelling evidence for the belief that biological aging is also a random process is that everything in the universe changes or ages in space-time without being driven by a purposeful program. Although there is no direct evidence that genes drive age changes, their critical role in longevity determination is indisputable.
There is a huge body of knowledge supporting the belief that age changes are characterized by increasing entropy, which results in the random loss of molecular fidelity, and accumulates to slowly overwhelm maintenance systems [1–4].
Both biological systems and inanimate objects incur change over time. Living systems, however, are, among other properties, distinguishable from inanimate objects, because a purposeful genetic program governs the changes that occur from their beginning until reproductive maturation. In inanimate objects, change is not programmed. It is continuous and never ending. Whether the changes that occur in inanimate objects are called age changes or not occurs because of the tendency for humans to view the physical world in anthropomorphic terms.
The common denominator that underlies all modern theories of biological aging is change in molecular structure and, hence, function. These changes are the result of entropic changes, which is now supported by the recent reinterpretation of the Second Law of Thermodynamics, where the belief that it only applies to closed systems has been overturned [5].
Entropy is the tendency for concentrated energy to disperse when unhindered regardless of whether the system is open or closed. The hindrance of entropic change is the relative strength of chemical bonds. The prevention of chemical bond breakage, among other structural changes, is absolutely essential for life. Through evolution, natural selection has favored energy states capable of maintaining fidelity in most molecules until reproductive maturation, after which there is no species survival value for those energy states to be maintained indefinitely.
The dispersal of energy may result in a biologically inactive or malfunctioning molecule. Energy dispersal is never entirely eliminated but it can be circumvented for varying time periods by repair or replacement processes. The internal presence of these repair or replacement processes represents a major difference between living and inanimate forms.
From the standpoint of a physicist, a lowered energy state is not necessarily disorder, because it simply results in the identical molecule with a lowered energy state. The fact that such a molecule might be biologically inactive may not concern the physicist, but it definitely does concern the biologist and, especially, the biogerontologist.
The aging process occurs because the changed energy states of biomolecules renders them inactive or malfunctioning. Identical events also occur before the aging phenotype appears, but repair and replacement processes are capable of maintaining the balance in favor of functioning molecules; otherwise, the species would vanish. After reproductive maturation, this balance slowly shifts to one in which molecules that lose their biologically active energy states are less likely to be replaced or repaired. The diminution of repair and replacement capability is further exacerbated, because the enormously complex biomolecules that compose the repair and replacement systems also suffer the same fate as their substrate biomolecules.
When the escalating loss of molecular fidelity ultimately exceeds repair and turnover capacity, vulnerability to pathology or age-associated diseases increases [1,3,6]. Immortal biological systems cannot exist, if for no other reason than molecular turnover (or dilution) insures that the molecules present at the beginning of a biological lineage are unlikely to be present in that lineage when it reaches Avogadro's Number of about 6 × 1023 cells. The only biological property that is long lasting on an evolutionary time scale is the message coded in information-containing molecules, but even that data is subject to mutation or change [7].
Although the loss of molecular fidelity is a random process, there is, nonetheless, a strong element of uniformity, in that errors will occur first in the same families of the most vulnerable molecules in similar cells, organs, or objects. The components of a system in which these molecules are a part then become the weakest link in that system. This accounts for the similarity in the aging phenotype as it progresses within species members.
Similar events occur in aging inanimate objects where, for example, automobiles of a particular make, model, and year of manufacture may have a greater probability of failure in a common weakest link, such as the electrical system. In another car of similar manufacture but different make, year, or model, molecules in the cooling or exhaust system will suffer age changes fastest and become the most probable system to fail first. There is, inevitably, a weakest link with the probability of failing first in a similar component of all complex entities. This “mean time to failure” for a cheap car might be six or seven years, and for newborns today in developed countries their mean time to failure is in the range of 75–85 years.
In humans in developed countries, the weakest links are the cells that compose the vascular system and those in which cancer is most probable. The molecular instability, or aging process, that occurs in these cells is the weakest link that increases vulnerability to these two leading causes of death. This is why knowing how fundamental age changes occur could lead to a better understanding of the etiology of all of the leading causes of death.
The “hypothesis that aging is due in part to mtDNA damage and associated mutations…[because the mitochondrion] generates most cellular ROS” [8] is an excellent example of one of the many possible active causes of the loss of molecular fidelity that characterizes the aging process. Both active and spontaneous entropic processes described above must be balanced by repair and turnover to insure species survival until reproductive success.
Recent studies done using bacteria seem to support the thesis, described above, that “damaged proteins” are the cause of age changes. When a bacterium like Escherichia coli divides by fission, one of the two daughter lineages is “damaged enriched” and the other has “low damage” [9]. The former are “non-culturable or genetically dead” while the latter are “reproductively competent.” In Caulobacter crescentus, replicative senescence has been observed [10], a phenomenon that we first described in normal human cells more than 45 years ago [11]. The phenomenon has also been reported to occur in E. coli and in Saccharomyces cerevisae [12]. The occurrence of replicative senescence in normal cells appears to be a universal biological phenomenon.