Cell death / apoptosis

Author(s): LeAnn Snow, MD, PhD

Originally published:09/14/2015

Last updated:09/14/2015


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:
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 survive1

Theories of aging:

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.1,2Examples of these theories include the free radical theory, mitochondrial theory, 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:

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.1,3 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, autophagy, or necrosis) 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.


Apoptosis & Cell Death

In this section, the cell death/removal processes will be described. Understanding of these processes is important for understanding the physical changes of normal aging.

Background: Cell damage and mitochondria
As noted above, normal aging is associated with increased accumulation of cellular damage.4Many 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)].5 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.6Mitochondria also are important organelles in the induction of apoptosis, autophagy and senescence.6

Apoptosis is the process of programmed cell death.7 In this process, damaged cells die and are removed by phagocytosis without triggering inflammation.7,8 The apoptosis signaling pathway is strongly regulated, with intricate interplay between anti-apoptotic and pro-apoptotic factors.7,8 It can be mediated by signaling of ROS-modified molecules.6

Apoptosis is a vital process in normal embryogenesis.7 It can facilitate organism survival after insult by removing damaged cells without inflammatory injury to the remaining cells.7 Research has found that human aging is associated with a decrease in apoptosis intensity, although much remains to be learned about the actual contribution of apoptosis to normal aging.7

Necrosis is the process of cell death due to injury from trauma, infection, extreme thermal stress, or other factors.8 In contrast to apoptosis, necrosis activates inflammation pathways that can be harmful to surrounding cells.

Senescence is the process by which damaged cells lose their ability to divide, but without cell death or neoplastic transformation.8 Senescent cells can contribute to an unhealthy environment around them by expressing inflammatory cytokines. DNA damage is a common initiator of the senescence pathway8. Cultured senescent cells are also typically apoptosis-resistant,7 but it is not known if this characteristic is manifested by cells in vivo.

The number of senescent cells has been found to be increased in aging tissues;7,8 increased serum inflammatory cytokines have also been found in human aging.7 The increase in senescent cells has been linked to the pro-inflammatory phenotype often seen with aging [senescence associated secretory phenotype [SASP]). 7 The higher numbers of senescent cells may also contribute to etiologies of age-related diseases, such as metabolic syndrome, and age-related macular degeneration, as well as to inflammation-related diseases of aging, such as atherosclerosis.8 Correlation has not yet been made between numbers of senescent cells and body-wide changes of normal aging.8

Autophagy is the process by which damaged molecules, organelles or cells are degraded enzymatically.6,8 The damaged entity is surrounded by a membrane and transported to the lysosome for digestion.6 Amino acids and other products of the digestion are then used for cell maintenance.4,5 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.8 Autophagy can be initiated by ROS-modified molecule signaling.5,6

Like apoptosis, autophagy is important in normal growth and development.6 Autophagy also decreases with normal aging5,6,7 followed by accumulation of malfunctioning mitochondria and proteins and other organelles.

Which pathway is used?
The relationship between autophagy, apoptosis, senescence, and necrosis appears to be dependent on the cellular context, and may be influenced by the severity of stress induced. Mild stress may foster autophagy or senescence, with moderate stress resulting in apoptosis, and severe stress causing necrosis. 8, 9 There is significant overlap in the proteins and molecular pathways involved in autophagy and apoptosis. 9

Tissue effects in aging

This section discusses the research findings regarding the relationships between tissue changes of normal aging and the processes of autophagy, apoptosis, senescence and necrosis. 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.

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.5

Osteocyte apoptosis increases with aging, and oxidative stress is the proposed trigger. This apoptotic pathway may be induced after failure of autophagy in rescuing damaged osteocytes. One of the proposed mechanisms for the effect of nitrogen-containing bisphosphonate medications is apoptosis-prevention for osteocytes and osteoblasts.

Intervertebral Disc:12
Aging in the disc is influenced by mitochondria-mediated apoptosis and resultant cell loss. Senescent cells have also been identified in human disc.

Skeletal Muscle:
Sarcopenia is the age-related decrease of muscle mass and muscle function, characterized by muscle atrophy and decrease in myofiber number.13 The loss of muscle cells is thought to be due primarily to mitochondria-mediated apoptosis.14 A unique feature of skeletal muscle is that myofibers are multinucleated. Therefore apoptosis of one nucleus and its associated cytoplasm may not cause death of the entire muscle cell, but rather result in myofiber atrophy 13,14,15

In muscles of aged experimental animals, aerobic exercise has been found to decrease components of apoptotic pathways, as well as to mitigate muscle atrophy.13 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. Few human studies are available, particularly in aging muscle.15

Nervous system:16
There is loss of alpha motor neurons from the spinal cord as aging proceeds, and the loss is due to oxidative stress and apoptosis. This motor nerve loss contributes to the muscle atrophy and decreased muscle cell number of sarcopenia. There is also loss of large axon fibers in peripheral nerves. Exercise training has not been shown to mitigate this axon loss, although such training can increase firing frequency in aging human motor nerves.

Immune System:7
Accumulation of senescent lymphocytes may contribute to a pro-inflammatory state in aging.


Research is progressing in the area of relationships between aging, apoptosis and stem cell biology. Another area of research focus is the search for pharmaceutically-modifiable reactions in the molecular pathways of apoptosis and senescence, with goal of improving health in aging and aging-related disease.


Much of the current understanding of biological aging has come from research in animal models, 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 may not be possible at this time. Much remains yet to be done in aging research regarding translation of animal model findings to human applications.


  1. Ljubuncic P, Reznick A. The evolutionary theories of aging revisited-a mini-review.  Gerontology. 2009; 55:205-216.
  2. Weinert BT, Timiras PS. Physiology of aging, Invited Review: Theories of aging. J Appl Physiol. 2003;95:1706-1716.
  3. Vetter N. The epidemiology of aging. In: Fillit HM, Rockwood K, Woodhouse K, eds. Brocklehurst’s Textbook of Geriatric Medicine and Gerontology. 7th ed. Philadelphia PA: Saunders-Elsevier; 2010:8.
  4. Wirawan E, Vanden Berghe T, Lippens S, Agostinis OP, Vandenabeele P. Autophagy: for better or for worse. Cell Research. 2012; 22:43-61.
  5. Green DR, Galluzzi L, Kroemer G. Mitochondria and the autophagy-inflammation-cell death axis in organismal aging. Science. 2011;333 (6046):1109-1112.
  6. Mammucari C, Rizzuto R. Signaling pathways in mitochondrial dysfunction and aging. Mech Ageing Dev. 2010; 131:536-543.
  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. Szumiel I. Autophagy, reactive oxygen species and the fate of mammalian cells. Free Radic Res. 2011;45(3):253-265.
  10. Sheydina A, Riordon DR, Boheler KR. Molecular mechanisms of cardiomyocyte aging. Clin Sci. 2011;121(8):315-329.
  11. Dominguez L, Di Bella G, Belvedere M, Barbagallo M. Physiology of the aging bone and mechanism of action of bisphosphonates. Biogerontology. 2011;12(5):397-408.
  12. Gruber HE, Watts JA, Hoelscher GL, Bethea BS, et al. Mitochondrial gene expression in the human annulus: in vivo data from annulus cells and selectively harvested senescent annulus cells. Spine J. 2011; 11(8):782-791.
  13. 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.
  14. Dirks-Naylor AJ, Lennon-Edwards S. Cellular and molecular mechanisms of apoptosis in age-related muscle atrophy. Curr Aging Sci. 2011;4(3):269-278.
  15. 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.
  16. 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.

Author Disclosures

LeAnn Snow, MD, PhD
Nothing to Disclose

Related Articles