The stem cell theory of aging postulates that the

aging process Ageing ( BE) or aging ( AE) 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. In ...

is the result of the inability of various types of

stem cell In multicellular organisms, stem cells are undifferentiated or partially differentiated cells that can differentiate into various types of cells and proliferate indefinitely to produce more of the same stem cell. They are the earliest type o ...

s to continue to replenish the tissues of an

organism In biology, an organism () is any living system that functions as an individual entity. All organisms are composed of cells (cell theory). Organisms are classified by taxonomy into groups such as multicellular animals, plants, and ...

with functional

differentiated cell Cellular differentiation is the process in which a stem cell alters from one type to a differentiated one. Usually, the cell changes to a more specialized type. Differentiation happens multiple times during the development of a multicellular ...

s capable of maintaining that tissue's (or organ's) original function. Damage and error accumulation in genetic material is always a problem for systems regardless of the age. The number of stem cells in young people is very much higher than older people and thus creates a better and more efficient replacement mechanism in the young contrary to the old. In other words, aging is not a matter of the increase in damage, but a matter of failure to replace it due to a decreased number of stem cells. Stem cells decrease in number and tend to lose the ability to differentiate into progenies or

lymphoid The lymphatic system, or lymphoid system, is an organ system in vertebrates that is part of the immune system, and complementary to the circulatory system. It consists of a large network of lymphatic vessels, lymph nodes, lymphatic or lymphoid o ...

lineages and myeloid lineages. Maintaining the dynamic balance of stem cell pools requires several conditions. Balancing proliferation and

quiescence Quiescence (/kwiˈɛsəns/) is a state of quietness or inactivity. It may refer to: * Quiescence search, in game tree searching (adversarial search) in artificial intelligence, a quiescent state is one in which a game is considered stable and unl ...

along with homing (''See''

niche Niche may refer to: Science *Developmental niche, a concept for understanding the cultural context of child development *Ecological niche, a term describing the relational position of an organism's species *Niche differentiation, in ecology, the ...

) and self-renewal of

hematopoietic stem cells Hematopoietic stem cells (HSCs) are the stem cells that give rise to other blood cells. This process is called haematopoiesis. In vertebrates, the very first definitive HSCs arise from the ventral endothelial wall of the embryonic aorta within ...

are favoring elements of stem cell pool maintenance while differentiation,

mobilization Mobilization is the act of assembling and readying military troops and supplies for war. The word ''mobilization'' was first used in a military context in the 1850s to describe the preparation of the Prussian Army. Mobilization theories and ...

and senescence are detrimental elements. These detrimental effects will eventually cause

apoptosis Apoptosis (from grc, ἀπόπτωσις, apóptōsis, 'falling off') is a form of programmed cell death that occurs in multicellular organisms. Biochemical events lead to characteristic cell changes (morphology) and death. These changes incl ...

. There are also several challenges when it comes to therapeutic use of stem cells and their ability to replenish organs and tissues. First, different cells may have different lifespans even though they originate from the same stem cells (''See''

T-cells A T cell is a type of lymphocyte. T cells are one of the important white blood cells of the immune system and play a central role in the adaptive immune response. T cells can be distinguished from other lymphocytes by the presence of a T-cell rec ...

and

erythrocytes Red blood cells (RBCs), also referred to as red cells, red blood corpuscles (in humans or other animals not having nucleus in red blood cells), haematids, erythroid cells or erythrocytes (from Greek ''erythros'' for "red" and ''kytos'' for "holl ...

), meaning that aging can occur differently in cells that have longer lifespans as opposed to the ones with shorter lifespans. Also, continual effort to replace the somatic cells may cause exhaustion of stem cells.

Research

Some of the proponents of this theory have been Norman E. Sharpless,

Ronald A. DePinho Ronald A. DePinho (born 1955) is an American physician and research scientist. He served as president of MD Anderson Cancer Center from 2011 to 2017. DePinho states that his concern for reducing the burden of cancer suffering became his life goal ...

, Huber Warner, Alessandro Testori and others. Warner came to this conclusion after analyzing human case of Hutchinson's Gilford syndrome and

mouse A mouse ( : mice) is a small rodent. Characteristically, mice are known to have a pointed snout, small rounded ears, a body-length scaly tail, and a high breeding rate. The best known mouse species is the common house mouse (''Mus musculus' ...

models of

accelerated aging Accelerated aging is testing that uses aggravated conditions of heat, humidity, oxygen, sunlight, vibration, etc. to speed up the normal aging processes of items. It is used to help determine the long-term effects of expected levels of stress wit ...

. Stem cells will turn into certain cells as the body needs them. Stem cells divide more than non stem cells so the tendency of accumulating damage is greater. Although they have protective mechanisms, they still age and lose function. Matthew R. Wallenfang, Renuka Nayak and Stephen DiNardo showed this in their study. According to their findings, it is possible to track male GSCs labeled with

lacZ The ''lactose'' operon (''lac'' operon) is an operon required for the transport and metabolism of lactose in ''E. coli'' and many other enteric bacteria. Although glucose is the preferred carbon source for most bacteria, the ''lac'' operon allows ...

gene In biology, the word gene (from , ; "...Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation'' or ''birth'' or ''gender'') can have several different meanings. The Mendelian gene is a ba ...

in ''Drosophila'' model by inducing recombination with heat shock and observe the decrease in GSC number with aging. In order to mark GSCs with lacZ gene, flip recombinase (Flp)-mediated recombination is used to combine a ubiquitously active

tubulin Tubulin in molecular biology can refer either to the tubulin protein superfamily of globular proteins, or one of the member proteins of that superfamily. α- and β-tubulins polymerize into microtubules, a major component of the eukaryotic cytoske ...

promoter followed by an FRT (flip recombinase target) site with a promotorless lacZ ORF (

open reading frame In molecular biology, open reading frames (ORFs) are defined as spans of DNA sequence between the start and stop codons. Usually, this is considered within a studied region of a prokaryotic DNA sequence, where only one of the six possible readin ...

) preceded by an FRT site. Heat shock is used to induce Flp recombinase marker gene expression is activated in dividing cells due to recombination. Consequently, all clone of cells derived from GSC are marked with a functional lacZ gene. By tracking the marked cells, they were able to show that GSCs do age. Another study in a mouse model shows that stem cells do age and their aging can lead to heart failure. Findings of the study indicate that

diabetes Diabetes, also known as diabetes mellitus, is a group of metabolic disorders characterized by a high blood sugar level ( hyperglycemia) over a prolonged period of time. Symptoms often include frequent urination, increased thirst and increased ap ...

leads to premature

myocyte A muscle cell is also known as a myocyte when referring to either a cardiac muscle cell (cardiomyocyte), or a smooth muscle cell as these are both small cells. A skeletal muscle cell is long and threadlike with many nuclei and is called a muscl ...

senescence and death and together they result in the development of

cardiomyopathy Cardiomyopathy is a group of diseases that affect the heart muscle. Early on there may be few or no symptoms. As the disease worsens, shortness of breath, feeling tired, and swelling of the legs may occur, due to the onset of heart failure. A ...

due to decreased muscle mass. Recent work has suggested that, although adult tissue stem cells may the key cell type in the aging process, they may contribute via reducing their differentiation rates, rather than via becoming exhausted. Under this model, when stem cells divide but do not differentiate, they produce an excess of daughter stem cells. This phenotype will be selected for, at the cellular level, if it is caused by heritable epigenetic changes or genetic mutations, and has the potential to overwhelm homeostatic regulation of cell numbers when organismal integrity is under reduced selection in later life. Behrens et al. have reviewed evidence that age-dependent accumulation of DNA damage in both stem cells and cells that comprise the stem cell microenvironment is responsible, at least in part, for stem cell dysfunction with aging.

Hematopoietic stem cell aging

Hematopoietic stem cell Hematopoietic stem cells (HSCs) are the stem cells that give rise to other blood cells. This process is called haematopoiesis. In vertebrates, the very first definitive HSCs arise from the ventral endothelial wall of the embryonic aorta within t ...

s (HSCs) regenerate the blood system throughout life and maintain homeostasis. DNA strand breaks accumulate in long term HSCs during aging. This accumulation is associated with a broad attenuation of DNA repair and response pathways that depends on HSC quiescence. DNA ligase 4 (Lig4) has a highly specific role in the repair of double-strand breaks by

non-homologous end joining Non-homologous end joining (NHEJ) is a pathway that repairs double-strand breaks in DNA. NHEJ is referred to as "non-homologous" because the break ends are directly ligated without the need for a homologous template, in contrast to homology direc ...

(NHEJ). Lig4 deficiency in the mouse causes a progressive loss of HSCs during aging. These findings suggest that NHEJ is a key determinant of the ability of HSCs to maintain themselves over time.

Hematopoietic stem cell diversity aging

A study showed that the clonal diversity of

s that produce blood cells gets drastically reduced around age 70 , substantiating a novel theory of ageing which could enable healthy aging.

Hematopoietic mosaic loss of chromosome Y

A 2022 study showed that blood cells' loss of the Y chromosome in a subset of cells, called 'mosaic loss of chromosome Y' (mLOY) and reportedly affecting at least 40% of 70 years-old men to some degree, contributes to

fibrosis Fibrosis, also known as fibrotic scarring, is a pathological wound healing in which connective tissue replaces normal parenchymal tissue to the extent that it goes unchecked, leading to considerable tissue remodelling and the formation of perma ...

, heart risks, and mortality in a causal way.

Hair follicle stem cell aging

A key aspect of hair loss with age is the aging of the

hair follicle The hair follicle is an organ found in mammalian skin. It resides in the dermal layer of the skin and is made up of 20 different cell types, each with distinct functions. The hair follicle regulates hair growth via a complex interaction between h ...

. Ordinarily, hair follicle renewal is maintained by the stem cells associated with each follicle. Aging of the hair follicle appears to be primed by a sustained cellular response to the DNA damage that accumulates in renewing stem cells during aging. This damage response involves the

proteolysis Proteolysis is the breakdown of proteins into smaller polypeptides or amino acids. Uncatalysed, the hydrolysis of peptide bonds is extremely slow, taking hundreds of years. Proteolysis is typically catalysed by cellular enzymes called protease ...

of type XVII

collagen Collagen () is the main structural protein in the extracellular matrix found in the body's various connective tissues. As the main component of connective tissue, it is the most abundant protein in mammals, making up from 25% to 35% of the whole ...

by neutrophil

elastase In molecular biology, elastase is an enzyme from the class of ''proteases (peptidases)'' that break down proteins. In particular, it is a serine protease. Forms and classification Eight human genes exist for elastase: Some bacteria (includin ...

in response to the DNA damage in the hair follicle stem cells. Proteolysis of collagen leads to elimination of the damaged cells and then to terminal hair follicle miniaturization.

Evidence against the theory

Diseases such as

Alzheimer's Alzheimer's disease (AD) is a neurodegenerative disease that usually starts slowly and progressively worsens. It is the cause of 60–70% of cases of dementia. The most common early symptom is difficulty in remembering recent events. As t ...

disease A disease is a particular abnormal condition that negatively affects the structure or function of all or part of an organism, and that is not immediately due to any external injury. Diseases are often known to be medical conditions that a ...

, end-stage renal failure and heart disease are caused by different mechanisms that are not related to stem cells. Also, some diseases related to hematopoietic system, such as

aplastic anemia Aplastic anemia is a cancer in which the body fails to make blood cells in sufficient numbers. Blood cells are produced in the bone marrow by stem cells that reside there. Aplastic anemia causes a deficiency of all blood cell types: red blood ...

and complete

bone marrow Bone marrow is a semi-solid tissue found within the spongy (also known as cancellous) portions of bones. In birds and mammals, bone marrow is the primary site of new blood cell production (or haematopoiesis). It is composed of hematopoietic ce ...

failure, are not especially age-dependent. Aplastic Anemia is often an adverse effect of certain medications but as such it cannot really be considered as evidence against the stem cell theory of aging. The cellularity of the bone marrow does decrease with age and can be usually calculated by the formula 100-age, and this seems consistent with a stem cell theory of aging. A dog study published by Zaucha J.M, Yu C. and Mathioudakis G., ''et al.'' also shows evidence against the stem cell theory. Experimental comparison of the engraftment properties of young and old marrow in a mammal model, the dog, failed to show any decrement in stem cell function with age.

Other theories of aging

The aging process can be explained with different theories. These are evolutionary theories, molecular theories, system theories and cellular theories. The evolutionary theory of ageing was first proposed in the late 1940s and can be explained briefly by the accumulation of mutations (

evolution of ageing Enquiry into the evolution of ageing, or aging, aims to explain why a detrimental process such as ageing would evolve, and why there is so much variability in the lifespans of organisms. The classical theories of evolution (mutation accumulation, ...

), disposable soma and

antagonistic pleiotropy hypothesis The antagonistic pleiotropy hypothesis was first proposed by George C. Williams in 1957 as an evolutionary explanation for senescence. Pleiotropy is the phenomenon where one gene controls for more than one phenotypic trait in an organism. Antagoni ...

. The molecular theory of ageing includes phenomena such as gene regulation (

gene expression Gene expression is the process by which information from a gene is used in the synthesis of a functional gene product that enables it to produce end products, protein or non-coding RNA, and ultimately affect a phenotype, as the final effect. The ...

), codon restriction,

error catastrophe Error catastrophe refers to the cumulative loss of genetic information in a lineage of organisms due to high mutation rates. The mutation rate above which error catastrophe occurs is called the error threshold. Both terms were coined by Manfred ...

, somatic mutation (accumulation of genetic material damage) and dysdifferentiation (

DNA damage theory of aging The DNA damage theory of aging proposes that aging is a consequence of unrepaired accumulation of naturally occurring DNA damage. Damage in this context is a DNA alteration that has an abnormal structure. Although both mitochondrial and nuclear ...

). The system theories include the immunologic approach to ageing, rate-of-living and the alterations in neuroendocrinal control mechanisms. (''See''

homeostasis In biology, homeostasis (British English, British also homoeostasis) Help:IPA/English, (/hɒmɪə(ʊ)ˈsteɪsɪs/) is the state of steady internal, physics, physical, and chemistry, chemical conditions maintained by organism, living systems. Thi ...

). Cellular theory of ageing can be categorized as

telomere A telomere (; ) is a region of repetitive nucleotide sequences associated with specialized proteins at the ends of linear chromosomes. Although there are different architectures, telomeres, in a broad sense, are a widespread genetic feature mos ...

theory, free radical theory (

free-radical theory of aging The free radical theory of aging (FRTA) states that organisms age because cells accumulate free radical damage over time. A free radical is any atom or molecule that has a single unpaired electron in an outer shell.Erbas M, Sekerci H. "Importance ...

) and

. The stem cell theory of aging is also a sub-category of cellular theories.

Footnotes

References

* * * * * * * * * * * * * * * * * {{DEFAULTSORT:Stem Cell Theory Of Aging Stem cells Theories of ageing Theories of biological ageing Proximate theories of biological ageing