Aging HyoungJinChoi 2024 Geromics Course

Definition 

Ageing (or aging in American English) is the process of becoming older. The term refers mainly to humans, many other animals, and fungi, whereas for example, bacteria, perennial plants and some simple animals are potentially biologically immortal.^[1] In a broader sense, ageing can refer to single cells within an organism which have ceased dividing, or to the population of a species.^[2]

In humans, ageing represents the accumulation of changes in a human being over time and can encompass physical, psychological, and social changes.^[3][4] Reaction time, for example, may slow with age, while memories and general knowledge typically increase. Ageing is associated with increased risk of cancer, Alzheimer's disease, diabetes, cardiovascular disease and many more.^[5][6] Of the roughly 150,000 people who die each day across the globe, about two-thirds die from age-related causes.

Current ageing theories are assigned to the damage concept, whereby the accumulation of damage (such as DNA oxidation) may cause biological systems to fail, or to the programmed ageing concept, whereby the internal processes (epigenetic maintenance such as DNA methylation)^[7][8] inherently may cause ageing. Programmed ageing should not be confused with programmed cell death (apoptosis).

Obesity has been proposed to accelerate ageing,^[9][10] whereas dietary calorie restriction in non-primate animals slows ageing while maintaining good health and body functions. In primates (including humans), such life-extending effects remain uncertain.

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Paper review

1) Hallmarkers of aging : An expanding universe

Summary

Aging is driven by hallmarks fulfilling the following three premises: (1) their age-associated manifestation, (2) the acceleration of aging by experimentally accentuating them, and (3) the opportunity to decelerate, stop, or reverse aging by therapeutic interventions on them. We propose the following twelve hallmarks of aging: genomic instability, telomere attrition, epigenetic alterations, loss of proteostasis, disabled macroautophagy, deregulated nutrient-sensing, mitochondrial dysfunction, cellular senescence, stem cell exhaustion, altered intercellular communication, chronic inflammation, and dysbiosis. These hallmarks are interconnected among each other, as well as to the recently proposed hallmarks of health, which include organizational features of spatial compartmentalization, maintenance of homeostasis, and adequate responses to stress.

in detail ​twelve hallmarks:

(1) the time-dependent manifestation of alterations accompanying the aging process. 
(2) the possibility to accelerate aging by experimentally accentuating the hallmark, and—most decisively—.
(3) the opportunity to decelerate, halt, or reverse aging by therapeutic interventions on the hallmark. 

PRIMARY
genomic instability
- The increased tendency for DNA mutations (changes) and other genetic changes to occur during cell division. Genomic instability is caused by defects in certain processes that control the way cells divide. It occurs in many types of cancer. These defects may include mutations in certain genes involved in repairing damaged DNA or mistakes that don’t get corrected when DNA is copied in a cell. They may also include defects such as broken, missing, rearranged, or extra chromosomes. Studying genomic instability may help researchers understand how certain diseases, such as cancer, form. This may lead to new ways to diagnose, treat, and prevent disease.
link : https://www.cancer.gov/publications/dictionaries/cancer-terms/def/genomic-instability

telomere attrition
- As cells divide, the telomere ends of chromosomes get shorter. Eventually, the enzyme that adds telomeric repeat sequences, telomerase, gets silenced and the telomeres are too short for cells to divide. Shortened telomeres are associated with aging cells that are senescent.

Telomeres at the ends of chromosomes, like all other sections of DNA, are prone to DNA damage, including double-strand breaks (DSBs). And unlike the rest of the chromosome, telomere DSBs aren’t fixed by the DNA repair pathway, as this would frequently lead to fused chromosomes and genomic instability. That’s why we have telomerase. However, telomerase expression is silenced in many adult cells, to curb rampant cell proliferation and tumorigenesis, and so telomeres get progressively shorter with age.
link : https://www.merckmillipore.com/KR/ko/life-science-research/genomic-analysis/Epigenetics-and-Nuclear-Function/Telomere-Attrition/jzWb.qB.RLAAAAFOrgM1lTAO,nav?ReferrerURL=https%3A%2F%2Fwww.google.com%2F

epigenetic alterations
- A change in the chemical structure of DNA that does not change the DNA coding sequence. Epigenetic alterations occur in the body when chemical groups called methyl groups are added to or removed from DNA or when changes are made to proteins called histones that bind to the DNA in chromosomes. These changes may occur with age and exposure to environmental factors, such as diet, exercise, drugs, and chemicals. They can affect a person’s risk of disease and may be passed from parent to child. Also called epigenetic variant and epimutation.

link : https://www.cancer.gov/publications/dictionaries/cancer-terms/def/epigenetic-alteration

loss of proteostasis
- Proteostasis is the dynamic regulation of a balanced, functional proteome. The proteostasis network includes competing and integrated biological pathways within cells that control the biogenesis, folding, trafficking, and degradation of proteins present within and outside the cell.[1][2] Loss of proteostasis is central to understanding the cause of diseases associated with excessive protein misfolding and degradation leading to loss-of-function phenotypes,[3] as well as aggregation-associated degenerative disorders.[4] Therapeutic restoration of proteostasis may treat or resolve these pathologies.[5]

Cellular proteostasis is key to ensuring successful development, healthy aging, resistance to environmental stresses, and to minimize homeostatic perturbations from pathogens such as viruses.[2] Cellular mechanisms for maintaining proteostasis include regulated protein translation, chaperone assisted protein folding, and protein degradation pathways. Adjusting each of these mechanisms based on the need for specific proteins is essential to maintain all cellular functions relying on a correctly folded proteome.

link : https://en.wikipedia.org/wiki/Proteostasis

disabled macroautophagy
- Autophagy refers to the various pathways used by cells to transport cytoplasmic substances to lysosomes for degradation. These pathways include macroautophagy, chaperone-mediated autophagy (CMA), and microautophagy. While CMA has been covered in the “Cell aggregates” section, little is known about the relevance of microautophagy in mammalian organismal aging, and this pathway remains poorly studied. Therefore, this discussion will only focus on macroautophagy, also commonly called simply as autophagy.


Figure 2. Autophagy process (source: Nakamura and Yoshimori 2018)

The process of autophagy can be broken down into the following steps:

Initiation: This step involves the activation of a complex of proteins called the ULK1 complex, which is regulated by several signaling pathways, including mTOR, AMPK, and IIS

Autophagosome formation and maturation: The process begins with the creation of an isolation membrane, or phagophore, which envelops the cytoplasmic component that needs to be broken down. This membrane then extends and seals itself, forming a double-membraned structure known as the autophagosome. As the autophagosome matures, it acquires various proteins and lipids essential for its eventual fusion with a lysosome.

Fusion and degradation:  In the final step, the autophagosome merges with a lysosome to create an autolysosome. Lysosomal enzymes then break down the contents of the autophagosome, and the resulting degradation products are released back into the cytoplasm for reuse by the cell.

Several animal models have shown a decline in autophagy with aging, while upregulating autophagy can increase lifespan. By targeting the components involved in each step above, autophagy can be stimulated, resulting in improvements in healthspan.

link : https://www.adanguyenx.com/longevity/autophagy

ANTAGONISTIC
deregulated nutrient-sensing
- Metabolic activities can put stress on our cells. Too much activity, and changes in nutrient availability and composition cause cells to age faster.

Metabolism and its byproducts, over time, damage cells via oxidative stress, ER stress, calcium signaling, and mitochondrial dysfunction. Therefore, organisms depend on multiple nutrient sensing pathways to make sure that the body takes in just the right amount of nutrition – not too much, not too little. However, these damaging events also deregulate the nutrient-sensing molecules and downstream pathways. A misguided hypothalamus may signal for greater food intake, then, when the body doesn’t really require it. Age-related obesity, diabetes and other metabolic syndromes result. To make things even worse, obesity- and diabetes-related chronic inflammation, operating via JNK and IKK crosstalk, can deregulate nutrient sensing further.

Probably because so many interdependent pathways link metabolism to aging, these are the pathways that have received the most intense focus in the search for anti-aging therapeutics. There was much excitement in the last decade around resveratrol and caloric restriction, the effects of which have now been shown to be limited to mice and other model organisms. Today, intermittent caloric restriction (i.e., fasting) is the only intervention that has been shown to extend human lifespan.

link : https://www.merckmillipore.com/KR/ko/life-science-research/genomic-analysis/Epigenetics-and-Nuclear-Function/Deregulated-Nutrient-Sensing/FsCb.qB.u04AAAFQ6t52i0ib,nav?ReferrerURL=https%3A%2F%2Fwww.google.com%2F

mitochondrial dysfunction
- A lack of energy production from mitochondria in your cells causes mitochondrial disease. Mitochondria are responsible for producing energy within your body. When your mitochondria don’t receive the instructions they need from your body’s DNA to make energy, it can damage your cells or cause them to die early. This affects how your organs and organ systems function, which leads to symptoms of the condition.

link : https://my.clevelandclinic.org/health/diseases/15612-mitochondrial-diseases

cellular senescence
-Cellular senescence is a state of permanent cell cycle arrest that was initially defined for cells grown in cell culture. Later on, this cell response was identified both in vitro and in vivo for cells subjected to different forms of stress, and more recently it has also been involved in physiological situations during development.

link :  https://www.sciencedirect.com/topics/medicine-and-dentistry/cellular-senescence

INTEGRATIVE
stem cell exhaustion
- At the moment of fertilisation, a cellular program launches to grow a new multicellular organism. This process, taking place before foetal development, is called embryogenesis and begins with a fertilised egg – a zygote. The zygote contains the 23 human chromosome pairs necessary to create a new person, one set from each parent. This zygote then undergoes multiple rounds of division to create a ball of cells called a blastocyst. Within this ball lies a cell mass consisting of embryonic stem cells, each with the ability to differentiate into one of many cell types within our bodies – this is called pluripotency. As we grow, the vast majority of our cells lose this ability to differentiate, but some pockets of cells do retain the ability to give rise to a limited set of cell types. This limited capacity to differentiate is called multipotency, and it helps us to renew and repair tissues across our body. The bulk of our cells are differentiated and actually don’t divide, instead being constantly replaced by a minority of proliferating cells. Haematopoietic stem cells in our bone marrow produce a constant supply of red and white blood cells, muscle stem cells stand at the ready to divide and repair damaged muscle tissue when needed, and dead skin cells are replaced on a daily basis by stem cells at the base of the epidermis. The nervous system and heart can be partly renewed but undergo minimal specific renewal in comparison to the rest of the body; new neurons can only form in certain areas. Stem cells are key to both providing new cells as old ones are lost and to correcting incurred wear and tear. Stem cell exhaustion refers to a decline in stem cell numbers and renewal capacity. Without stable populations of proliferating stem cells, tissues and organs lose their ability to recover from damage and begin to fail.

link : https://www.gowinglife.com/what-is-stem-cell-exhaustion-the-hallmarks-of-ageing-series/

altered intercellular communication
- Cells, as they age, show an increase in self-preserving signals that result in damage elsewhere. Altered intercellular communication with aging contributes to decline in tissue health.

Like the decline in stem cell renewal, the age-dependent changes in intercellular communication are integrated effects of the other hallmarks of aging. In particular, senescent cells trigger chronic inflammation that can further damage aging tissues.

The cdc42 GTPase pathway, in addition to the NF-κB pathway, has been shown to increase inflammation in senescent cells; in fact, knocking down cdc42 expression actually increases longevity in C. elegans. GTPases also integrate signals from cell-cell junctions, which may break down in aging tissues.

At an organ system level, the aging hypothalamus drives changes in neurohormone signaling, which in turn affects food intake and metabolism. Since the hypothalamus also regulates sleep cycles, these changes can inhibit DNA repair, exacerbating the aging phenotype.

link : https://www.merckmillipore.com/KR/ko/life-science-research/antibodies-assays/antibodies-overview/Research-Areas/cell-signaling/Altered-Intercellular-Communication/C.qb.qB.O48AAAFQe592i0hr,nav

chronic inflammation
- Chronic inflammation is also referred to as slow, long-term inflammation lasting several months to years. Generally, the extent and effects of chronic inflammation vary with the cause of the injury and the ability of the body to repair and overcome the damage. This activity reviews the pathophysiology of chronic inflammation and highlights the role of the interprofessional team in taking steps to control the pathology.

link : https://www.ncbi.nlm.nih.gov/books/NBK493173/

dysbiosis
- In this chapter, we have attempted to comprehensively define the role of dysbiosis and expression of disease. Dysbiosis has been defined and categories of dysbiosis considered. The importance of normal intestinal colonization of the gut during the neonatal period has been emphasized for proper development of immunologic and metabolic intestinal function, and lifelong health. The factors that influence gut colonization and the consequences of improper factors leading to dysbiosis and disease have been considered. Finally, in the context of our understanding of dysbiosis future studies to define dysbiotic signatures of disease and to suggest possible approaches to affecting dysbiosis are necessary.

link : https://www.sciencedirect.com/topics/medicine-and-dentistry/dysbiosis




link : https://www.cell.com/cell/fulltext/S0092-8674(22)01377-0?_returnURL=https%3A%2F%2Flinkinghub.elsevier.com%2Fretrieve%2Fpii%2FS0092867422013770%3Fshowall%3Dtrue

 

2) Epigenetic clock: A promising biomarker and practical tool in aging

link : https://www.sciencedirect.com/science/article/pii/S1568163722001854?via%3Dihub