Hallmarks of aging
Hallmarks of aging are distinctive features of the biological aging process. Such deteriorations have been enumerated with the goal of extending healthspan or lifespan: in Aubrey de Grey's Strategies for Engineered Negligible Senescence, and in the 2013 paper "The Hallmarks of Aging".
Strategies for Engineered Negligible Senescence
The Strategies for Engineered Negligible Senescence (SENS) are a classification of potential life extension therapies by the type of age-related damage they target. It was created by Aubrey de Grey in 2000 and published in his 2007 book Ending Aging. The seven types of damage listed are:
- Cell loss: fewer cells in tissue, causing deterioration, due to impaired dead-cell replacement by stem cells
- Extracellular junk: old proteins (example: Alzheimer's plaque) impairing cell/tissue function
- Extracellular crosslinks: proteins binding together, impairing their functions
- Cells resisting death: accumulated cells harmful in abundance (example: senescent cells)
- Mitochondrial mutations: harmful mtDNA variations due to waste from cellular energy conversion
- Intracellular junk: breakdown-resistant molecules incapacitating cellular cleaning mechanisms
- Nuclear mutations: harmful DNA or epigenetic variations, especially cancer
The Hallmarks of Aging
"The Hallmarks of Aging" is a paper written by Carlos López-Otín, Maria Blasco, Linda Partridge, Manuel Serrano, and Guido Kroemer and published in 2013 in the journal Cell. The nine hallmarks presented are:
- Genomic instability: DNA damage that can lead to mutations, cancer, and harmful senescent cells
- Telomere attrition: gradual shortening of caps on ends of chromosomes, limiting cell division and leading to low cell counts
- Epigenetic alteration: gene expression changes increasing cancer risk
- Proteostasis loss: protein building failure, accumulating malformed proteins, causing disease (example: Alzheimer's)
- Nutrient-sensing deregulation: four deregulated nutrient-sensing pathways, each with an associated protein
- Mitochondrial dysfunction: mitochondria failing to provide energy and releasing a harmful kind of oxygen
- Cellular senescence: accelerating accumulation of old, dysfunctional cells
- Stem cell depletion: deficiency of cells with improved signalling that replace lost or damaged cells
- Intercellular communication alteration: disease-causing change in signalling between cells
- de Grey, Aubrey; Rae, Michael (2007). Ending Aging: The Rejuvenation Breakthroughs that Could Reverse Human Aging in Our Lifetime. ISBN 0-312-36706-6.
- López-Otín, Carlos; Blasco, Maria A.; Partridge, Linda; Serrano, Manuel; Kroemer, Guido (6 June 2013). "The Hallmarks of Aging". Cell. 153 (6): 1194– 1217. doi:10.1016/j.cell.2013.05.039.
- "RepleniSENS". SENS Research Foundation. "Some of these damaged cells are repaired, but others are either destroyed, or forced into a dysfunctional ‘senescent’ state where they can no longer divide, or commit ‘cellular suicide’ (apoptosis) for the greater good of the body. Some of the lost cells are replaced by the pools of specialized, tissue-specific stem cells, but the degenerative aging process makes these stem cell pools less effective at repair over time."
- "AmyloSENS". SENS Research Foundation. "Extracellular junk is accumulations of sticky, malformed proteins that no longer serve their function, but instead impair cell or tissue function by their presence. [...] The most well-known form of extracellular junk is beta-amyloid: the stifling, web-like material that forms plaques in the brains of patients with Alzheimer’s disease, and also (more slowly) in everyone else’s, and impairs cognitive function."
- "GlycoSENS". SENS Research Foundation. "Crosslinks act like molecular 'handcuffs,' taking two neighboring proteins that were previously able to move independently of one another and binding them together, impairing their function in the same way that occurs to participants in a three-legged race."
- "ApoptoSENS". SENS Research Foundation. "Pushing these cells to undergo such transformations is favored by evolution because it meets short-term needs, and having a few of these abnormal cells in the body for is nearly harmless. But the number of these cells in our tissues gradually rises over time, until by our fifth decade or so they begin to reach levels that are harmful to normal tissue function. [...] The original and most well-studied sort of cells of this type are what are usually called 'senescent' cells."
- "MitoSENS". SENS Research Foundation. "Just like real power plants, mitochondria generate toxic waste products in the process of 'burning' food energy as fuel – in this case, spewing out highly-reactive molecules called free radicals, which can damage cellular structures. [...] At worst, a free radical 'hit' to the mtDNA can cause major deletions in its genetic code, eliminating the mitochondria’s ability to use the instructions to make proteins that are critical components of their energy-generating system."
- "LysoSENS". SENS Research Foundation. "Cells have a variety of systems for breaking down and recycling such unwanted materials, allowing them to clear garbage out of the way and reuse the raw materials. [...] However, sometimes these constituents are so badly fused together that not even the lysosome is able to tear them apart. And if something can’t be broken down in the lysosome, there’s nowhere else for it to go: it just stays there until either the lysosome disastrously ruptures, or the cell itself is destroyed."
- "OncoSENS". SENS Research Foundation. "Mutations are damage to the DNA sequence itself, whereas epimutations are damage to the “scaffolding” of that DNA, which controls how and when genes get turned on in the cell. [...] The one that most people know about is cancer, which is the result of a series of (epi)mutations that happen in sequence in the cell, leading to its uncontrolled growth. Other kinds of (epi)mutations also occur in our cells over time, and some scientists have worried that these non-cancer-causing (epi)mutations might also contribute in different ways to age-related disease and disability. But there is good reason to believe that there aren’t enough such mutations to actually have a meaningful impact on our health."
- "Why we age: Genomic Instability". Lifespan.io. "As described in the Hallmarks of Aging, genomic instability is the result of gradual damage to DNA in ways that are not naturally repaired. This is a root cause of aging, and it leads to genetic mutations and an increased risk of cancer. [...] Eventually, the number of these damaged cells reaches a point where tissue or organ function is compromised. [...] Unfortunately, some cells evade apoptosis, taking up space in the tissue and pumping out inflammatory signals that damage the local tissue. These cells are known as senescent cells, another one of the hallmarks."
- "Why we age: Telomere Attrition". Lifespan.io. "The Hallmarks of Aging describes telomere attrition (or telomere shortening), which is the gradual loss of the protective caps of our chromosomes, and is one of the aging processes. Telomere attrition limits the number of times our cells can divide, slowly leading to dwindling populations of cells in vital organs."
- "Why we Age: Epigenetic Alterations". Lifespan.io. "Epigenetic alterations, as described in the Hallmarks of Aging, are age-related changes in gene expression that harm the fundamental functions of cells and increase the risk of cancer and other age-related diseases."
- "Why we Age: Loss of Proteostasis". Lifespan.io. "The Hallmarks of Aging describes the loss of proteostasis as the failure of the protein building machinery of the cell and the accumulation of misfolded proteins, which is one of the root causes of age-related diseases, including Alzheimer’s disease."
- "Why we Age: Deregulated Nutrient Sensing". Lifespan.io. "As described in the Hallmarks of Aging , the four pathways of nutrient-sensing regulate metabolism and influence aging. The four associated key protein groups are IGF-1, mTOR, sirtuins, and AMPK."
- "Why we Age: Mitochondrial Dysfunction". Lifespan.io. "As they age, mitochondria lose their ability to provide cellular energy and release reactive oxygen species that harm cells."
- "Why we Age: Cellular Senescence". Lifespan.io. "The Hallmarks of Aging describes dysfunctional senescent cells, which promote other hallmarks and encourage other cells to become senescent, causing them to accumulate with age."
- "Why we Age: Stem Cell Exhaustion". Lifespan.io. "Stem cells perform a wide range of functions, including beneficial signaling that improves tissue function, regulation and health as well as the replacement of damaged or lost red blood cells, white blood cells, and solid tissues."
- "Why we Age: Altered Intercellular Communication". Lifespan.io. "Altered intercellular communication, as described in the Hallmarks of Aging, is the change in signals between cells that can lead to some of the diseases and disabilities of aging."
- What Is Aging? (explanation of aging hallmarks)