The Hallmarks of Aging Outlined for Laypeople

More than a decade after the SENS view of the causes of aging was first assembled, the noted Hallmarks of Aging paper attempted another catalog of the important processes of aging. There is some overlap between the two, though I'd categorize portions of the Hallmarks of Aging list as secondary or later processes in aging, not primary causes, and thus poor targets for intervention. In both cases the aim of putting together such a list is to treat aging as a medical condition, though the Hallmarks of Aging authors were much more oblique when it came to stating the end goal of extended healthy human life spans, something that continues to be an issue in many parts of the research community. The goal of medical control over aging and radical extension of healthy life spans is important and desirable, and the failure of much of the scientific community to clearly say as much is why we need advocacy organizations like the SENS Research Foundation and Life Extension Advocacy Foundation, the latter of which is revamping their web presence at the moment. Among the new content going up at the Life Extension Advocacy Foundation site is this tour of the Hallmarks of Aging outline, explained for laypeople:

According to modern science, aging is the accumulation of damage that the body cannot completely eliminate, due to the imperfections of its protection and repair system. As a result, bodily functions start to deteriorate, leading ultimately to the development of age-related diseases. Aging comprises of a number of distinct and interconnected processes which we will explore briefly. Once you begin to understand the processes of aging it becomes possible to understand the ways we might intervene against them in order to treat and prevent age-related diseases, hence enabling people to live healthier lives for longer.

Genomic instability is considered one of the main causes of aging. Somatic cells are constantly exposed to a range of sources of DNA damage. When DNA is damaged, some proteins can stop being produced or can have the wrong shape, which, in turn, compromises the function of the cell. When there are many cells with this kind of damage in the organ, some important body functions can start to deteriorate. DNA damage during aging appears to be a stochastic process. However, chromosomal regions such as the telomeres have a somewhat more predictable pattern of deterioration. Telomere loss is technically a subset of genomic instability but warrants its own category as a form of aging damage due to this more predictable nature. Telomeres are a protective cap at the end of a chromosome. Each time a cell divides, telomeres get increasingly shorter and once they become critically short the cell ceases to divide and enters replicative senescence, better known as the Hayflick limit. Importantly, as telomeres shorten they influence the gene expression profile (the production of proteins) of a cell changing it from a functionally young one to an old one.

Changes to gene expression patterns (deactivation of useful genes and activation of potentially harmful ones) are a key influence in aging. Generally speaking, these changes (known as epimutations) lead to detrimental changes in gene expression patterns. Epigenetic alterations are a complex and not fully understood process. They can be considered almost like a program in a computer, but in this case it is the cell, not the computer, being given instructions. Ultimately these changes contribute to the cell moving from an efficient "program" of youth to a dysfunctional one of the old age. However the process appears to be plastic and is not the one-way process people once assumed. Indeed recent research shows that epigenetic alterations can be made to reverse this process of aging to restore youthful function and increase lifespan.

Proteostasis is the process by which cells control the abundance and folding of the proteins - building blocks of each cell. Proteostasis consists of a complex network of systems that integrates the regulation of gene expression, signaling pathways, molecular chaperones and protein degradation systems. Aging is linked to the impairment of proteostasis and the various quality control systems it incorporates. Even during regular operation misfolding of proteins can occur and they are immediately broken down and recycled. However with aging and the decline of proteostasis misfolded proteins increase and lead to aggregation.

The scientific evidence to date suggests that anabolic signaling (internal alarm about the abundance of nutrients) appears to accelerate aging, and that decreased nutrient signaling is shown to extend lifespan. We see from experiments that adjusting signalling using substances like rapamycin to mimic limited nutrient availability can increase lifespan in mice. Consistent with deregulated nutrient sensing, we see that dietary restriction increases lifespan in various species. There is also increasing evidence for the healthspan benefits of dietary restriction in humans.

Mitochondria are the "power plants" of the cells: they convert the energy-rich nutrients into energy store molecules that directly power the biochemical reactions in the cell. Unlike any other part of the cell, mitochondria have their own DNA (mtDNA), especially vulnerable to damage from free radicals. A free radical strike to the mtDNA can cause deletions in its genetic code, destroying the mitochondria's ability to make proteins that are critical components of their energy-generating system. Without the ability to produce cellular energy the normal way, these damaged mutant mitochondria enter into an abnormal metabolic state to survive. This state produces little energy, and generates large amounts of waste that the cell cannot metabolize. Strangely, the cell favours keeping these defective, mutant mitochondria, while recycling normal ones. Whilst this only happens to a few cells in our body, these cells do a large amount of damage to the body as a whole.

As the body ages, increasing amounts of cells enter a state of senescence. Senescent cells do not divide or support the tissue they are a part of, but instead emit a range of potentially harmful signals known collectively as the senescent associated secretory phenotype (SASP). Senescent cells normally destroy themselves via a programmed process called apoptosis and they are removed by the immune system. However, the immune system weakens with age, increasing numbers of these senescent cells escape this process and build up. By the time people reach old age significant numbers of these senescent cells have accumulated in the body and cause havoc, driving the aging process further and increasing the risk of diseases.

Every day, our cells are damaged. Some of these damaged cells are successfully repaired and keep serving the body. Others are either completely destroyed via apoptosis, or become dysfunctional and enter a 'senescent' state where they can no longer divide. Some of these lost cells are replaced from reserves of tissue-specific stem cells, but the aging process makes these stem cell pools less effective at repairs over time, and eventually those reserves run out. Over the passage of time, long-lived tissues, such as those in the brain, heart, and skeletal muscles, begin to progressively lose cells, and their function becomes increasingly compromised. Muscles weaken, and don't respond to exercise. The brain loses neurons, leading to cognitive decline and dementia. Ultimately the loss of reserves of replacement cells leads to the failure of tissue repair and is a significant driver of aging.

Aging causes changes to communication outside of the cell, which ultimately affects the function of all cells and tissues. Cellular communication has endocrine, neuroendocrine or neuronal origins. One of the best known age-related changes in intercellular communication is chronic inflammation (often called 'inflammaging'), which implies an increasingly rising background level of inflammation as we age. In addition to inflammatory signals, the so called bystander effect, in which senescent cells induce senescence in neighboring cells through the toxic signals they give off, is also a part of altered intercellular communication.

A suspected cause of degenerative aging is the accumulation of sugary metabolic wastes known as advanced glycation end-products (AGEs). These are wastes that are in some cases hard for our metabolism to break down fast enough or even at all. Some types, such as glucosepane, can form cross-links, gumming together important proteins like those making up the supporting extracellular matrix scaffold. The properties of elastic tissues (skin and blood vessel walls) derive from the particular structure of the extracellular matrix, and cross-links degrade that structure, preventing it from functioning correctly. AGE presence contributes to blood vessel stiffening with age, and is implicated in hypertension and diabetes.

Link: http://dx.doi.org/10.1016/j.cell.2013.05.039

Comments

hee hee you dont miss a trick do you Reason :) We also added crosslinks to the list as Hallmarks misses this out and we feel it should be in there. This article is slated for periodic review so will grow over time as new data comes in.

Posted by: Steve Hill at January 3rd, 2017 2:02 PM

I watched this video last night where Aubrey mentions this paper:
https://m.youtube.com/watch?v=0oAVPCxOKxM

But the seven processes that Aubrey shows as the SENS hallmarks look different from what I've seen before. I don't see senescence cell clearance, or don't understand which process is the same as that. (Please see video, not this Cell paper.)

Posted by: NY2LA at January 3rd, 2017 4:56 PM

@NY2LA senescence cell clearance is exactly the same in Hallmarks and is identified as "Cellular Senescence". They cite the campisi work and so on and we mention the more up to date work by Barker, Kirkland etc... etc...

Posted by: Steve Hill at January 3rd, 2017 6:07 PM

@Michael. Yes, Michael, that is what I mean, and you've answered my question. Thank you. (I was too lazy to play the video again to find it, so thanks for finding it.)

Posted by: NY2LA at January 4th, 2017 12:35 AM

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