Anti-aging dilemma: to restore the hardware or to reinstall the software?

Abstract

Sinceitsearlydays,thevalueofdecipheringthehumanDNAhasbeenseenprimarilyinextractingthe set of messages that run the cells that constitute the body. In common understanding, thesemessages are encoded in DNA and transcribed as cell-specific sets of RNAs, some of which aretranslatedtoproteins,thenmodifiedwithvariouspost-translationaladd-onsmadeofsugars,lipidsand other moieties. This complex chain of events is further complicated by multi-layered possi-bilities for the modifications allowed at every step–epigenetics for DNA, editing for RNAs andtherecentlydiscoveredphenomenonofnon-templatepolypeptideextensionallowedbyribosomes(Shen et al., 2015). It seems that when looked at as a whole, the DNA, and all the messages associ-ated with DNA, do not look like a blueprint, or even a clear set of instructions, but rather a messydraft or a stack of notes that are scribbled all over and full of ambiguities.However, let us hack through the majority of the “omics” and look upon the set of smallmolecules known as metabolites, and the budding discipline of Metabolomics that researches thetrueunderpinningsoftheabundantlycomplexmechanicsofthelivingcell.Itisworthwhiletonotethat,toasomewhatdefineddegree,thecellwilltoleratethelossofageneorchangesinthelevelsofRNAs or even the most important of proteins, while even slight deregulation of the levels of someof the smallest metabolites leads to immediate and catastrophic consequences. The potassium ionandATPmaybeusedastheprimaryexamplesofsmallestmoleculescapableofelicitingasystemicresponse.Accordingtoourcalculation,amere0.5%increaseinthetotalcontentofpotassiumchlo-ride, one of the most common electrolytes in the human body, leads to immediate cardiac arrest.TheconsequencesofthedepletionofATPmaymanifestasavarietyofailments,withtheirdurationinversely proportional to the severity of the defect. Aging, in particular, is associated with a declinein the efficiency of oxidative phosphorylation and an increase in the risk of resulting pathologies.Of course, there are other small molecules, possibly not as well-known as ATP, but still indispens-able and irreplaceable. In particular, the metabolites derived from the amino acid tryptophan havethe capacity for similar dramatic alteration of system-wide function. Most pertinent to the topicof this discussion, the changes in metabolic profiles are considered as drivers for the pathogene-sis of age-associated disorders, including Alzheimer’s disease (Tacutu et al., 2010; Demetrius andDriver, 2013; Jia et al., 2014; Obre and Rossignol, 2015). It also is of note that metabolites are notasabundantascommonlystudiedspeciesofproteinsandRNAs.Hence,theworldofmetabolitesisimmensely easier to comprehend than the overly complicated world of other famous “omics.” Thelatter point is extremely important, as it provides a possibility for the use of a powerful reduction-ist approach without falling into ill-fitting or over-fitting of the underlying model, a well-knownperpetual source of entrapment.Letuscomparetheliving(andaging)cell,withitsendless“omics”-scalelayersofinterconnectedcomponents, to modern computers. Computer hardware is a collection of interconnected physicaldevices used in or with your machine. One of these parts may wear itself out and die; however,