20130606
Carlos López-Otín, Maria A. Blasco, Linda Partridge, Manuel Serrano, Guido Kroemer
https://www.cell.com/cell/fulltext/S0092-8674%2813%2900645-4

It is valuable to reduce the effects of aging to prevent aging related disease. The hallmarks of aging are an attempt to categorize somatic and stem cell damage that occur with time:

genomic instability
telomere attrition
epigenetic alterations
loss of proteostasis
deregulated nutrient-sensing
mitochondrial dysfunction
cellular senescence
stem cell exhaustion
altered intercellular communication

Part of the challenge is unraveling ways in which these hallmarks are related to each other.

Cancer and aging share common origins: the accumulation of cellular damage. Thus, the categorization of the underlying mechanisms that drive cancer, by Hanahan and Weinberg in 2000, and again in 2011, has also helped give insight into the hallmarks of aging.

For example, “atherosclerosis and inflammation involve uncontrolled cellular overgrowth or hyperactivity.”

Each hallmark meets the following criteria:

1. manifested during normal aging
2. experimental aggravation should accelerate aging
3. experimental amelioration should retard aging

The last criterion is the most difficult to achieve. It's possible that amelioration of one hallmark can also reduce the others.

Exogenous and endogenous threats drive genetic lesions. Endogenous threats include ROS (Reactive Oxygen Species), replication errors, and spontaneous reactions. Exogenous threats include anything from the environment, such as radiation. These legions are mostly fended by various repair and integrity-checking mechanisms in the cells.

Increasing the effectiveness of these mechanisms in mice has been shown to increase healthspan, as in the case of transgenic mice with an overexpression of BubR1.

Mutated or dysfunctional or senescent cells can be cleared by apoptosis or by the immune system. However, the number of senescent cells accumulate with age.

Genetic lesions are “highly diverse and include point mutations, translocations, chromosomal gains and losses, telomere shortening, and gene disruption caused by the integration of viruses or transposons.”

(the following just covers transposons)

Repetitive elements may comprise over two-thirds of the genome. (Koning et al 2011)¹⁾ These are thought to be caused by mobile genetic elements such as retrotransposons, which cause gene duplication events.

Transposons are selfish genetic elements, yet serve functions that are still being discovered.

Mitochondria are the aerobic power generators of a cell. Different cell types have different number of mitochondria, from zero in a red blood cell, to thousands in a liver cell.

Mitochondria is theorized to have been an independent organism that was absorbed by a larger organism, ending in a symbiosis from which we evolved. Thus, mitochondria have their own DNA, referred to as mtDNA.

MtDNA does not follow the rules of Mendelian inheritance. With rare exception, mtDNA is inherited exclusively from the mitochondria in the maternal egg cell. Because of the nature of this inheritance, even though there were many different mtDNA types at one time in history, there is now only one. Thus there was a single woman, referred to as Mitochondrial Eve from which all other women have inherited their mtDNA.

Over time, many of the genes in mtDNA were replaced or incorporated as genes in the cell nucleus. The mitochondrial genes located in the cell nucleus are transcribed and translated into proteins that are then imported into the mitochondria from the cytoplasm. There are around 1100 genes that are imported from the nucleus into the mitochondria in this way. Around a quarter of these, around 250, are for the maintenance and expression of the genes in the mitochondria.

There are 37 genes left in the mtDNA of humans, where it takes the form of a supercoiled circle. “This raises a question: why would eukaryotic cells invest more than 250 proteins to be able to make just a handful of them inside mitochondria? This question is intimately linked to another one: why mtDNA has been so carefully maintained during evolution?”

Also, unlike nuclear DNA, which has a single copy of its genome, there are many copies of mtDNA within a mitochondria. As noted earlier, there are many mitochondria per cell. “The actual number of mtDNA varies between cell types and is dependent on the energy demands within each cell. Any mutations in the mtDNA can co-exist with wild-type copies, a condition called heteroplasmy. The mutant mtDNAs do not exert a biochemical phenotype on a cell until the mutant load reach a certain level. The threshold of mutant/wild type can vary depending on the specific mutation and the cell type.” (Lee and Wei 2011)²⁾

“Although mtDNA was initially considered to be naked, unprotected, and vulnerable to damage, research over the last decades has shown that mtDNA is protein-coated and packaged into nucleoids.” (Szczepanowska and Trifunovic 2015)³⁾ Nonetheless, the protection is not as effective, and the mutation rate for somatic mtDNA is several orders of magnitude greater than that of nuclear DNA.

Originally, the Mitochondrial Theory of Aging proposed that oxidative damage increased exponentially with time: “Accumulation of these mtDNA mutations could result in dysfunction of the respiratory chain, leading to increased ROS production in mitochondria and subsequent accumulation of more mtDNA mutations. This vicious cycle has been proposed to account for an increase in oxidative damage during aging, which leads to the progressive decline of cellular and tissue functions as a result of insufficient supply of energy and increased susceptibility to apoptosis.” (Lee and Wei 2011)⁴⁾

When oxidative damage to DNA occurs and is not correctly repaired, there is one point mutation that happens more frequently. Oxidative damage to DNA can thus be traced as larger percentages of G → T mutations. Mounting evidence suggests the mutations occur during errors in mtDNA synthesis, rather than oxidative damage, and that the mutations that are seen to accumulate, occurred early in life: “Our results indicate that most somatic mtDNA mutations occur as replication errors during the rapid amplification of mtDNA during embryo-genesis and do not result from damage accumulation in adult life.” (Payne et al 2011)⁵⁾ “A continuously dividing tissue like liver may show a different pattern of accumulation of mtDNA point mutations with age in comparison with a postmitotic tissue such as brain or heart.” (Payne et al 2011)⁶⁾

“…given that there are hundreds of genes in nuclear genome bigger that the whole mtDNA, it is remarkable how this small piece of DNA can cause so many different metabolic diseases, be causatively linked to numerous age-associated disease and influence aging process itself.” (Szczepanowska and Trifunovic 2015)⁷⁾

Is there a separate process for maintaining mtDNA integrity in germ-line cells? There must be a way of keeping mutations in check, if lineages of mtDNA are so well kept that it is possible to trace populations by their mtDNA to a mitochondrial eve.

Alternate review:
https://www.leafscience.org/hallmarks-of-aging-mitochondrial-dysfunction/

Not only does DNA decline, but so does the nucleus that surrounds it. The nuclear lamina provides a scaffold for tethering chromatin and protein complexes that maintain genomic stability. If genes that make up the nuclear lamins are mutated, accelerated aging can occur, as in the case of a mutated prelamin A (aka progerin) which causes Hutchinson-Gilford and Nestor-Guillermo progeria syndromes. Laminar progerin has also been detected in normal human aging, and may be linked to telomere dysfunction. A decline in the levels of another laminar protein, Lamin B1, has been found to be useful as a marker for cell senescence.

In mice with progeria syndrome, treatments that reduce the effects of the disease have increased lifespan, including stem cell therapy that corrects the LMNA mutation. “Further studies are necessary to validate the idea that reinforcement of the nuclear architecture can delay normal aging.”

The protective end caps of DNA molecules are called telomeres, and they shorten with cell divisions or some strand repairs. Telomerase is an enzyme that can add length to the telomeres, but it is not produced in most somatic cells. Loss of telomeres has been shown to be the cause of cellular senescence.

DNA repair machinery is unable to see the end of the DNA double helix because telomeres are covered by shelterin. Damage to the telomeres is thus irreparable, even in the presence of telomerase, and also causes cellular senescence and apoptosis. In animal models, both deficiency in telomerase or shelterin components leads to loss of tissue-regenerative capability.

Genetically modified animals with shortened or lengthened telomeres lead shorter or longer lifespans, respectively. Premature aging of telomerase-deficient mice can be reverted by reactivating telomerase in the already aged mice. “Moreover, normal physiological aging can be delayed without increasing the incidence of cancer in adult wild-type mice by pharmacological activation or systemic viral transduction of telomerase. In humans, recent meta-analyses have indicated a strong relation between short telomeres and mortality risk, particularly at younger ages.”

Chromatin is composed of DNA and the proteins that help package and protect it. The packaging is made of histone proteins, which are like tupperware for DNA. Changes in the chromatin affect how DNA is expressed. Gene expression, which includes running a program coded for morphogenesis and growth, continues to change with age.

Chromatin changes include histone methylation and acetylation, with research showing that aging brings about consistent regions that have increased or decreased amounts of these molecular markers. The question unanswered is if the changes are a continuation of the morphogenic program, or if the changes are haphazard degradation of the chromatin in certain regions that are susceptible.

Histone modifications affect the way genes are expressed: “A histone modification is a covalent post-translational modification (PTM) to histone proteins which includes methylation, phosphorylation, acetylation, ubiquitylation, and sumoylation. The PTMs made to histones can impact gene expression by altering chromatin structure or recruiting histone modifiers.” ⁸⁾ The DNA within the chromatin can also be chemically marked.

Scientists have a lot to cover in understanding gene expression as a function of histone modification. However, there is a principle that a tightly packed region of chromatin keeps the DNA inaccessible to other molecules, such as the machinery that would transcript the DNA into RNA. There are regions of tightly-packed chromatin known as heterochromatin, where genes are mostly silenced. Some genes are silenced as intended, as in the case of the cell differentiation. Some genes tend towards being silenced as part of aging, with deleterious effects.

As mentioned earlier, mitochondria produce power for the cell. The citric acid cycle, or krebs cycle, is a process that occurs in the mitochondria for energy production. The process optimally produces 38 ATP, or adenosine triphosphate molecules, per cycle, which is the energy currency of the cell. When the phosphorylated ends of ATP are used up, AMP, or adenosine monophosphate, is left.

There is a sensor called AMPK, which senses the ratio between AMP and ATP in the cell. AMPK, or AMP-activated protein kinase, “stimulates energy generating processes such as glucose uptake and fatty acid oxidation and decreases energy consuming processes such as protein and lipid synthesis.” (Richter and Ruderman 2009)⁹⁾

“AMPK plays an important role to explain the therapeutic benefits of metformin, thiazolidinediones and exercise, which form the cornerstones of the clinical management of type 2 diabetes and associated metabolic disorders.” (Canto et al 2009)¹⁰⁾

During the krebs cycle, NADH is produced, which fuels the electron transport chain within the mitochondria to produce a portion of the ATP, with NAD+ as a byproduct.

There is a class of enzymes called sirtuins, which play a role in various gene expressions, which are dependent on NAD+. The seven sirtuins in mammals have a highly conserved version of the ancestral sirt2 found in c. elegans, which when overexpressed extended the life of the worms by 70%. Not only are the functions that sirtuins serve many and complex, so are the drivers that propel sirtuins to complete those functions. However, all sirtuins are dependent on the levels of NAD+.

“Because of the NAD+ dependency of their activity, changes in NAD+ levels regulate the function of the whole sirtuin family. In fact, the sensing of NAD+ levels forms the basis for sirtuins to function as metabolic and nutritional sensors.” (2016 Buler, Andersson, and Hakkola)¹¹⁾

The mode of action of sirtuins is mainly deacetylating lisine residues on various proteins (see table below, sourced from (Dang 2014)¹²⁾)

“Sirtuins or Sir2 (silent information regulator 2)-related enzymes have originally been defined as a family of nicotinamide adenine dinucleotide-dependent enzymes that deacetylate lysine residue on various proteins. Certain sirtuins have in addition an ADP-ribosyltransferase activity. The sirtuins are remarkably conserved throughout evolution from archaebacteria to eukaryotes. The mammalian sirtuins SIRT1–SIRT7 are implicated in a variety of cellular functions ranging from gene silencing, over the control of the cell cycle and apoptosis, to energy homeostasis. On a whole-body level, the wide range of cellular activities of the sirtuins suggests that they could constitute therapeutic targets to combat metabolic, neurodegenerative, and proliferative diseases.” (Yamamoto et al 2007)¹³⁾

https://www.ahajournals.org/doi/10.1161/CIRCRESAHA.118.312498

(UNDER CONSTRUCTION)