Author(s): LeAnn Snow, MD, PhD
Originally published: September 14, 2015 Last updated: June 1, 2020
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OVERVIEW AND DESCRIPTION

The understanding of biological aging is important to the physiatrist for a number of reasons. First, care of older adults is often a large part of a physiatrist’s practice, whether it is in the setting of neurological, orthopedic or cardiac rehabilitation, musculoskeletal clinic, or wellness consultation. Second, although physiatrists most often treat persons with diseases of aging, the underlying context of normal biological aging may well influence the older adult’s response to treatment and may differ somewhat from treatment responses of younger adults.

Biology of Aging, some Basics:

Definition of aging:1

Biological aging is identified as a combination of many complex biological processes that are:

  1. universal (applicable to all members of a species regardless of environment)
  2. intrinsic (contained within the organism)
  3. deleterious
  4. progressive
  5. cumulative
  6. cause of decline in the organism’s capacity to survive

Theories of aging: 1,2

Scientific knowledge remains incomplete with regard to the specific mechanisms of biological aging. There are many theories of aging, but none of them explains all aspects of aging. Examples of these theories include the free radical theory, mitochondrial theories, telomere shortening, and hormonal theories. The reader is referred to other sections of PM&R Knowledge NOW for more detail on these theories.

Aging and homeostasis, a matter of balance:1,2

A common thread in many of the theories of aging is that aging is associated with a disruption of the body’s homeostasis, the balance between damage and repair. Damage occurs during general cellular function and can target DNA, proteins, or lipids. It can be caused by extrinsic factors such as toxins, or intrinsic factors such as free radicals. This damage is usually efficiently detected and repaired in young individuals, with little effect on overall cellular or organism function. Several theories of aging posit that aging results when the body is not able to make sufficient repairs, and cellular function is adversely affected by accumulation of genetic mutations, dysfunctional proteins or by altered membranes.

In addition to making repairs, organisms have several means by which damaged molecules or cells are removed so that healthy function can be maintained. These processes include cell death (apoptosis, necrosis, or autophagy) and induction of cellular senescence. The aim of this section of PM&R Knowledge NOW is to summarize characteristics of these cellular removal processes, and to identify ways in which they have been found to contribute to normal aging.

RELEVANCE TO CLINICAL PRACTICE

Apoptosis, necrosis, autophagy and senescence

In this section, the cell death and senescence processes will be described. Understanding of these processes contributes to insight on normal biological aging and diseases of aging.

Background: Cell damage and mitochondria 3,4,5

As noted above, normal aging is associated with increased accumulation of cellular damage. Many types of stress can cause cellular damage, including low oxygen levels, DNA alterations, low nutrient levels, and oxidative stress [exposure to increased levels of reactive oxygen species, (ROS)]. Damage from these stressors can include DNA mutations, protein unfolding, and oxidation of lipids in membranes, all of which can impair cellular function. Because mitochondria are sites of high ROS production, they are key organelles in the aging process. Mitochondria also are important organelles in the induction of apoptosis, autophagy and senescence.

Apoptosis4,5,6,7,8

Apoptosis is the process of programmed cell death. In this process, damaged cells self-destruct, and are removed by phagocytosis without triggering inflammation. Apoptosis can occur via a number of intracellular signaling pathways; ROS-modified molecules can serve as triggers and/or apoptotic signaling molecules.   The apoptosis pathways are strongly regulated, with intricate interplay between anti-apoptotic and pro-apoptotic factors.     

Apoptosis is a vital process in normal embryogenesis and in maturation of the immune system It also facilitates organism survival by removing damaged cells without inflammatory injury to remaining cells. Research has found that apoptosis is often decreased human aging. Much remains to be learned about the actual contribution of apoptosis to normal aging.

Necrosis5,8

Necrosis is the process of cell death due to injury from trauma, infection, extreme thermal stress, or other factors.In contrast to apoptosis, necrosis activates inflammation pathways that can be harmful to surrounding cells.

Autophagy3,5,6,7,8

Autophagy is the process by which damaged molecules, organelles or cells are degraded enzymatically. The damaged entity is surrounded by a membrane and transported to the lysosome for digestion. Amino acids and other products of the digestion are then used for cell maintenance. Autophagy may or may not result in cell death. For example, if specific damaged proteins or mitochondria are autophagically removed, the process may actually assist in cell survival rather than in cell death.

Like apoptosis, autophagy is important in normal growth and development. Autophagy also decreases with normal aging which can result in accumulation of malfunctioning proteins, mitochondria and other organelles.

Senescence5,7,8,9,10,11

Senescence is the process by which damaged cells lose their ability to divide, but without cell death or neoplastic transformation. Similar to apoptosis, senescence is an important process in embryogenesis; it is also in wound healing. However, senescent cells can contribute to an unhealthy environment around them by expressing inflammatory cytokines [senescence associated secretory phenotype [SASP]. DNA damage is a common initiator of the senescence pathway. Cultured senescent cells are also typically apoptosis-resistant, but it is not known if this characteristic is manifested by cells in vivo.

Molecular markers of senescent cells have been found to be increased in many aging tissues of animal models and humans. This increase is thought to indicate increased numbers of senescent cells in aging, but confirming evidence is needed. The increase in numbers of senescent cells has been linked to the pro-inflammatory phenotype often seen with aging. Increased serum inflammatory cytokines have also been documented in human aging. The higher numbers of senescent cells may also contribute to etiologies of inflammation-related diseases of aging, such as atherosclerosis. Correlation has not yet been made between numbers of senescent cells and body-wide changes of normal aging.

Which pathway is used?4,5,6

The relationship between apoptosis, necrosis, autophagy and senescence is variable. The process is used by a cell depends on the specific tissues and cells involved, and may also be influenced by the severity of the inciting cellular stress. Milder stress may foster autophagy or senescence, with moderate stress resulting in apoptosis, and severe stress leading to necrosis.

Tissue effects in aging

This section discusses research findings regarding the relationships between tissue changes of normal aging and the processes of apoptosis, necrosis, autophagy, and senescence. Much of the current knowledge on this topic is derived from animal models. Extensive research remains yet to be done in human cells and tissues. The reader is referred to the Biology of Aging section of PM&R Knowledge NOW for more information on general organ-related changes of normal aging.

Heart3,5,12

The total number of cardiac myocytes decreases by as much as 30% with age; apoptosis is the primary pathway in this decrease. The heart is not able to regenerate or replace all these lost cells, so the remaining cells tend to hypertrophy. Specific inciting factors for this apoptosis are not known, although accumulated mitochondrial gene mutations appear to contribute.

Autophagy is also important for removal of damaged mitochondria in the cardiac myocytes. Exercise has been found to increase autophagy in the myocardium, and therefore may be a mechanism by which exercise is cardioprotective.

Bone13,14

Estrogen is anti-apoptotic for osteoblasts, and pro-apoptotic for osteoclasts. Thus age-related estrogen decline may contribute to bone loss via a shift in the balance between programmed cell death and survival of these two cell types. Although increased senescence markers have been documented in bone of older persons, not enough is known yet to make any firm conclusions about the contribution of senescence to age-related bone loss in humans. 

Intervertebral Disc15

Damaged proteins and DNA have been identified in aging human discs, as have apoptotic and senescent cells. Elevated levels of senescence markers have also been identified in aged human disc, thought to indicate increased numbers of senescent cells in older discs vs. younger ones. Further study is needed to better define specifically how apoptosis and senescence relate to functional changes in aging disc tissue.

 Skeletal Muscle16,17,18,19,20

Sarcopenia is the age-related decrease of muscle mass and muscle function, characterized by muscle atrophy and decreased myofiber number. A full understanding has yet to be reached regarding the etiologic complexities of this condition. However, it has been reported that there is a decrease in skeletal muscle autophagy with aging, particularly in autophagy for damaged mitochondria (mitophagy). There is also an increase is apoptosis. This alteration in balance between muscle repair and cell death promotes accumulation of damaged mitochondria and associated increased release of ROS, as well as decreased clearance of ROS-mediated cellular injury. There is very little experimental data to date regarding cellular senescence in aging skeletal muscle.

In muscles of aged experimental animals, aerobic exercise has been found to decrease components of apoptotic pathways, and increase components of autophagy pathways as well as to mitigate muscle atrophy. Chronic training also has been found to decrease ROS production in skeletal muscle, a decrease in oxidative stress. This oxidative stress reduction may decrease muscle apoptosis; however, more study is needed here.  

Nervous system 17,19,21,22,23

Structural mitochondrial abnormalities have been documented in pre-synaptic axons of aged mice. DNA damage and ROS-mediated mitochondrial dysfunction have also been documented in aging alpha motor neurons; such stressors can lead to apoptotic demise of these neurons. This motor nerve loss contributes to the muscle atrophy and decreased muscle cell number of sarcopenia Additionally, mitophagy is decreased in aging motor neurons, which may also contribute to alpha motor neuron loss due to accumulation of damaged organelles and proteins. Data is quite limited regarding the presence or functional significance of senescent cells in aging CNS.

Immune System 5,7

In aging, there is an increase in lymphocyte apoptosis,which is thought to contribute to a decreased number of T lymphocytes.Accumulation of senescent lymphocytes may contribute to a pro-inflammatory state in aging.

CUTTING EDGE/UNIQUE CONCEPTS/EMERGING ISSUES

Research is progressing in the area of relationships between aging, apoptosis, senescence and stem cell biology. Another area of research focus is the search for pharmaceutically-modifiable reactions in the molecular pathways of apoptosis and senescence (senotherapeutics, senolytics), with goal of improving health in aging and aging-related disease. Work with such compounds is primarily in pre-clinical stages.9,10,14

GAPS IN KNOWLEDGE/EVIDENCE BASE

As stated above, much of the current understanding of aging-related apoptosis and senescence has come from research in animal models or in vitro cell studies. Many of these models are highly specialized and genetically modified. Much less research has been done in non-modified animal models, or in humans.9,10 Such gaps in knowledge are in part due to difficulties inherent in doing longitudinal or tissue-based studies of human aging. Animal research has provided valuable information for understanding human aging, even though full translation of findings is not possible at this time.

Another knowledge gap is that there is currently not a specific laboratory assay that conclusively identifies senescent cells in humans.9,10,11,14 In order to obtain reliable study results and to formulate solid conclusions, improved assays are needed.

REFERENCES

  1. da Costa JP, Vitorino R, Silva G, Vogel C, et al. A synopsis on aging—Theories, mechanisms and future prospects. Ageing Res Rev. 2016; 29:90-112.
  2. Lopez-Otin C, Blasco M, Partridge L, Serrano M, Kroemer G. The hallmarks of aging. Cell.2013;153(6):1194-1217.
  3. Green DR, Galluzzi L, Kroemer G. Mitochondria and the autophagy-inflammation-cell death axis in organismal aging. Science. 2011;333 (6046):1109-1112.
  4. Arguelles S, Guerrero-Castilla A, Cano M, Munoz M, Ayala A. Advantages and disadvantages of apoptosis in the aging process. Ann NY Acad Sci. 2019; 1443:20-33.
  5. Tower J. Programmed cell death in aging. Ageing Res Rev.2015;23:90-100.
  6. Redza-Dutordoir M, Averill-Bates DA. Activation of apoptosis signalling pathways by reactive oxygen species. Biochimica et Biophysica Acta. 2016;1863:2977–2992.
  7. Salminen A, Ojala J, Kaarniranta K. Apoptosis and aging: increased resistance to apoptosis     enhances the aging process. Cell Mol Life Sci. 2011;68:1021-1031.
  8. Haines D, Juhasz B, Tosaki A. Management of multicellular senescence and oxidative stress. J Cell Mol Med. 2013;17(8):936-957.
  9. Childs BG, Durik M, Baker DJ, van Deursen JM. Cellular senescence in aging and age-related disease: from mechanisms to therapy. Nat Med. 2015;21(12):1424-1435.
  10. He S, Sharpless, NE. Senescence in Health and Disease. Cell. 2017;169:1000-1011.
  11. Ferrucci L, Gonzalez-Freire M, Fabbri E, Simonsick A et al. Measuring biological aging in humans: A quest. Aging Cell. 2020;19:e13080. https ://doi.org/10.1111/acel.13080  
  12. Sheydina A, Riordon DR, Boheler KR. Molecular mechanisms of cardiomyocyte aging. Clin Sci. 2011;121(8):315-329. 
  13. Gregson CL. Bone and joint aging. In: Fillit HM, Rockwood K, Woodhouse K, eds. Brocklehurst’s Textbook of Geriatric Medicine and Gerontology. 7th Ed. Philadelphia PA:Saunders-Elsevier;2017:123.
  14. Pignolo RJ, Samsonraj RM, Law SF, Wang H, Chandra A. Targeting cell senescence for the treatment of age-related bone loss. Curr Osteoporos Rep 2019;17:70-85
  15. Vo, N. V., Hartman, R. A., Patil, P. R., Risbud, M. V., et al.. Molecular mechanisms of biological aging in intervertebral discs. Journal of Orthopaedic Research. 2016; https://doi.org/10.1002/jor.23195
  16. Marzetti E, Calvani R, Bernabei R, Leeuwenburgh C. Apoptosis in skeletal myocytes: a potential target for interventions against sarcopenia and physical frailty-a mini-review. Gerontology. 2012;58(2):99-106.  
  17. Alway SE, Mohamed JS, Myers MJ. Mitochondria initiate and regulate sarcopenia. Exerc. Sport Sci. Rev.2017;45(2):58–69.
  18. Cartee GD, Hepple RT, Bamman MM, Zierath JR. Exercise Promotes Healthy Aging of Skeletal Muscle. Cell Metab. 2016;23:1034-1047.
  19. Larsson L, Degens H, Li M, Salviati L, et al. Sarcopenia: Aging-Related Loss of Muscle Mass and Function. Physiol Rev. 2019; 99: 427–511.
  20. Quadrilatero J, Always S, Dupont-Versteegden E. Skeletal muscle apoptotic response to physical activity: potential mechanisms for protection. Appl Physiol Nutr Metab. 2011;36(5):608-617.
  21. Aagaard P, Suetta C, Caserotti P, Magnusson SP, Kjaer M. Role of the nervous system in sarcopenia and muscle atrophy with aging: strength training as a counter measure. Scan J Med Sci Sports. 2010;20(1):49-64.
  22. Garcia ML, Fernandez A, Solas MT. Mitochondria, motor neurons and aging. J Neurol Sci. 2013; 330: 18–26.
  23. Baker DJ, Petersen RC. Cellular senescence in brain aging and neurodegenerative diseases: evidence and perspectives. J Clin Invest. 2018;128(4):1208-1216.

Original Version of the Topic

LeAnn Snow, MD, PhD. Cell death/apoptosis. 9/14/2015

Author Disclosures

LeAnn Snow, MD, PhD
Nothing to Disclose