New paper hypothesizes aging to be a result of intrinsic flaws in the software.
Aging occurs due to the accumulation of various cellular and molecular damage over time, and leads to deterioration of physical function and mental capacity, as well as increasing vulnerability to several diseases such as cancer, cardiovascular diseases, type II diabetes, neurodegenerative diseases, infectious diseases, and resulting, ultimately, in death.
While we have a pretty good handle on the end results of aging, the why of aging has generated as much discussion, with several theories having been proposed to explain why aging occurs. Among them, damaged-based theories are the most widely accepted – after all, the word age is right there in damage! These theories hypothesize that different types of molecular damage, such as unwanted chemical modifications, by-products of metabolism and others, impact important cellular components such as mitochondria, telomeres, genomes and proteins and ultimately drive aging.
In recent years, epigenetic clocks have determined that hypermethylation and hypomethylation of several methylation sites can accurately predict human chronological age – they are also capable of predicting mortality risk in humans. Epigenetic clocks can be set to back zero through reprogramming with Yamanaka factors, but whether they are drivers or passengers of aging is still unknown.
The information theory of aging has proposed that aging can be associated with decay or loss of information. As per this theory, loss of epigenetic or genetic information with age along with DNA damage can lead to aging. Damage or error to one or more biological hardware including the DNA can drive the process of aging. This hardware comprises tissues, organs, cells and their structures.
Longevity.Technology: The process of aging might not be due to inevitable molecular damage but instead due to certain intrinsic factors in the software. Researchers define this software to be the genetic program or the DNA code that determines how a single cell becomes an adult human being. They hypothesize that aging might not be due to the accumulation of molecular damage in the hardware but rather due to flaws in the software.
Now in a new paper published in Genome Biology, Dr João Pedro de Magalhães discusses the benefits of considering aging in this way, as well as acknowledge the limitations .
The software program and aging
The developmental software program that is encoded in the DNA comprises a sequence of information that helps to produce a reproductively competent adult (and hopefully competent in other ways!). However, it is not completely understood how a single cell develops into an embryo and finally into an adult comprising billions of cells with different functions and identities. Some genetically regulated processes during development can become harmful later in life resulting in degeneration and loss of function.
Although the mechanism and biological basis of epigenetic clocks are not fully understood, the running of developmental software programs is associated with epigenetic changes; multiple types of epigenetic changes, such as methylation, chromatin structure and histone modifications, consist of information on the running of the developmental software program. Another reason that supports that the developmental software program drives aging is that it is not a random process but rather a gradual and predictable process with a few exceptions. Additionally, aging changes also do not vary significantly among individuals. The developmental program can also explain why aging occurs faster in some closely related species even under optimal environmental conditions.
Cancer as an exception
Cancer is one of the most important age-related diseases that occurs due to random and stochastic damage. It is erratic and occurs mostly due to random DNA mutations and damage. Many studies have reported that older people have billions of cells with oncogenic mutations.
Since cancer is pretty much inevitable given the number of cells and the number of cell replications, there is a strong evolutionary selection to prevent cancer in young animals such as shorter telomeres and a slower mutation rate accumulation. The developmental software program must prevent cancer through the reduction of cancer-prone cells or controlling cell functions associated with tumorigenesis.
Impact of manipulating aging
Dietary, genetic, and pharmacological manipulations of aging and longevity are major breakthroughs in geroscience. Over 2000 genes and 1000 drugs have been reported to modulate longevity in model organisms. However, not all longevity modulations impact the aging process.
The GH/IGF1 pathway and dietary restriction are two major interventions that slow down the developmental software program as well as aging . Another pharmacological intervention is rapamycin whose intake during early years can retard the developmental software program and thereby aging.
Resetting the clock
Cell reprogramming and reproduction are seen as way to restart the software. Yamanaka factors can reset the software program and reverse cellular aging. However, the mechanism by which the software is reset during reproduction, induced pluripotency and somatic nuclear transfer is not fully understood, and the technology is still very much to be viewed as “don’t try this at home”.
Some recent studies indicate inducing pluripotency with Yamanaka factors in vivo can be harmful. On the other hand, partial reprogramming that allows the rejuvenation of cells without dedifferentiation is a promising alternative. Partial reprogramming can induce a software rewind that shifts the epigenome to a previous developmental stage which unlike software restart maintains the context of the cell  – rolling back to a previous version, as it were, rather than wipe and reset.
Unresolved questions and aging as a software design flaw
Although this study hypothesizes aging to be a software design flaw, there is still a lot more to understand. Firstly, aging needs to be seen as a program rather than an inevitable, spontaneous damage. If aging phenotypes are ingrained in developmental programs, then integration of developmental data into the models of aging and age-related diseases will be necessary. It is also important to understand how information encoded in the DNA sequence turns an embryo into an adult and then causes it to age and die.
This hypothesis proposes that the cells know how to avoid molecular damage and aging but due to flaws in the software they stop doing so – or are unable to do so – later in life. However, how the progression of the developmental software program triggers aging at the molecular and cellular levels is unclear. As de Magalhães points out, understanding the biology of aging will help to understand the cause of various age-related diseases. Additionally, the outcome of understanding and tackling software design flaws will be useful for the development of interventions.
Previous theories have suggested that the accumulation of molecular damage to the hardware is the main cause of aging. However, humans are not just chips and circuit boards. They develop from a single cell to a fully functional adult, and development is a well-regulated program serves to get us to reproduction but then becomes detrimental and results in aging.
This hypothesis emphasizes aging to be a result of the developmental software design flaw. Decoding the software and the flow of epigenetic information is required to understand aging, as well as what causes age-related diseases, and this will help us to develop accurate interventions to improve the healthspan and longevity of humans.