Author(s): Sunil K Jain, MD, Sohil Sheth, BS
Originally published: September 14, 2015 Last updated: August 17, 2023
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Overview And Description

The understanding of biological aging is important to the physiatrist for several 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 patients 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 aging1

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

  • Universal (applicable to all members of a species regardless of environment)
  • Intrinsic (contained within the organism)
  • Deleterious
  • Progressive
  • Cumulative
  • Cause of decline in the organism’s capacity to survive

Theories of aging1,2

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 balance1,2

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.

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.

Apoptosis4,5,6,7,8,33

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.

One of the clinically relevant topics about apoptosis has to do with wound healing. Wound healing is done in a stepwise manner. After an injury, the body initiates the homeostasis and coagulation phase, which begins immediately. This is swiftly followed by the inflammation phase. Subsequently, the migration and proliferation phase take place, facilitating the healing process. Finally, during the remodeling phase, new skin is formed, completing the recovery process. Apoptosis is occurring throughout all these phases to ensure that products of no use from the previous phase are destroyed and don’t hinder the next phase. It is crucial that apoptosis is kept at an equilibrium, too much can cause over excessive tissue destruction leading to a failure in wound healing; too little can cause excessive tissue growth and a potential for cancer. However, manipulation of apoptosis in cases of too much or too little tissue growth during the process of wound healing is a field of therapeutic promise and is currently in trials.

Another clinically relevant topic of apoptosis is frailty. Frailty in old age refers to a condition where older adults become more fragile, weaker, and less able to recover from health challenges. It is not solely due to aging but involves a combination of physical, psychological, and social factors that increase their vulnerability to adverse outcomes. In the past, frailty has been highly linked with an increase in apoptosis using animal models, however human clinical trials were still pending. Interestingly, in newer human studies, it is shown that while animal models have an increase in apoptosis in the frail animals, humans had no difference in apoptosis between those who were frail and those were not. While the study listed many possible limitations which could have skewed the data, it is still a surprising finding and highlights the importance of clinical trials before the consideration of therapeutic potential.

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 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.

Senescence5,7,8,9,10,11,24,25,32

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, such as p16, SA-b-gal, and DDR, 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. Previously, there has been a lack of correlation between senescence cells and body-wide changes of normal ageing; however recent studies have shown a decrease in age related organ deterioration and an increase in lifespan. In one study, mice encoded with Cdkkn2a, which when induced, leads to apoptosis of p16-expressing cells, were shown to increase the lifespan of the mice, male and female. It also delayed natural age-related deterioration of organs including the kidneys, heart, and fat. This animal model indicates therapeutic potential in the realm of reducing p16 or possibly other biomarkers of senescent cells, and in recent years, the use of senotheraputics have become increasingly more popular for the treatment of age-related diseases such as atherosclerosis, cardiovascular dysfunctions, etc. 

The production senescence cells have been majorly linked to the progression of age-related diseases which has begged the question whether the halt or destruction of these cells have the potential to attenuate this process. Research has proven the therapeutic use of the halt or destruction of these senescent cells via the use of either senomorphics or senolytics respectively. Here is a list that provides that current senotheraptuics that either has been FDA approved or that still awaits approval.

Table 1: Senotheraptics available32

Senolytics FDA approved:Senolytics with no approval:
Ouabain
Digoxin
Dasatinib
Alvespimycin
Panobinostat  		Quercetin
Fisetin
Piperlongumine
EF24 curcumin analog
Curcumin
ABT-263
ABT-737
A1331852
UBX1325
UBX0101
P5091
Geldanamycin
Tanespimycin
FOXO4-DRI
MitoTam
Senomorphics FDA approved:Senomorphics with no approval:
Metformin
Ruxolitinib
Cortisol
Corticosterone
Loperamide
Niguldipine		KU-60019
NBD peptide
Mmu-miR-2910-3p

Which pathway is used?4,5,6

The relationship between apoptosis, necrosis, autophagy, and senescence is variable. The process 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.

Bone13,14,26

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. Previously, there was no conclusive data about the contributions of senescence to age-related bone loss in humans, however newer studies on age-related osteoporosis show that mice with marked reduction of p16 or treated JAK inhibitors were shown to have a higher bone mass and better architecture compared to controls. P16 is a well-known biomarker for senescent cells while JAKi inhibit proinflammatory secretomes from senescent cell. This indicates that senescent cells may be a major culprit in age-related osteoporosis, however human trials are still to be conducted if there is to be any therapeutic considerations. It has also been noted in the same study that in vitro, osteoblast activity was impaired while osteoclast activity was induced via senescent cells which indicates the possible mechanism of action, but in-vivo studies must still be done.

Intervertebral Disc15,27,28

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. Recently, the molecular pathways for the effects of senescent cells on the functional changes in aging disk tissue have been discovered. During ageing, intervertebral disk undergo senescence via the activation of the p53-p21-retinoblastoma pathway. Senescent cells decrease the self-renewal ability of IVD, destroy the microenvironment, and produce degrading enzymes, all contributing to IVD destruction. Prevention of pro-senescent activity among this pathway may be a possible therapeutic to IVD degeneration and should be furthered studied.

Skeletal Muscle16,17,18,19,20,29

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. 

A recent study in rat models have shown therapeutic potential towards spermidine, a natural polyamine, in conjunction with exercise to dampen age-related skeletal muscle atrophy. This works via the induction of autophagy through the AMPK-FOXO3a pathway and the reduction of apoptosis, leading to the protection of skeletal muscle. While this study shows promise, human trials must be conducted before therapeutic considerations. 

Nervous system 17,19,21,22,23,30

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.

Recent breakthroughs in senescent cell research have allowed the discovery of senescent cells being a major part in age neurodegeneration. This was discovered in vivo and progeroid models which were able to show an accumulation of senescent cells in the CNS as well the senolysis being a causative factor of the neurodegenerative diseases, both of which supports senescence having a critical role in age-related neurodegenerative diseases. This research indicates the need for clinical trials to address whether a reduction in senescent cells in the CNS would lead to better outcomes for age-related neurodegeneration.

Immune System 5,7,31

In aging, there is an increase in lymphocyte apoptosis, which is thought to contribute to fewer T lymphocytes. Accumulation of senescent lymphocytes may contribute to a pro-inflammatory state in aging. Recent studies on the senescence of immune cells have shown that an age induced senescent immune system plays a causal role in system ageing. This was tested using mice models, who had their Ercc1 gene removed, which eventually caused immunosenescence. These mice were shown to have an impaired immune function as well as an increase in non-lymphoid organ senescence and damage. Senescent cell therapeutics continues to be one of the most promising aspects of research in the realm of cell death, and this stands with respect to the immune system.

Cutting Edge/Unique Concepts/Emerging Issues

Research is progressing in 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 currently possible.

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.
  24. Baker, D., Childs, B., Durik, M. et al. Naturally occurring p16Ink4a-positive cells shorten healthy lifespan. Nature 530, 184–189 (2016). https://doi.org/10.1038/nature16932
  25. Calcinotto A, Kohli J, Zagato E, Pellegrini L, Demaria M, Alimonti A. Cellular Senescence: Aging, Cancer, and Injury. Physiol Rev. 2019 Apr 1;99(2):1047-1078. doi: 10.1152/physrev.00020.2018. PMID: 30648461.
  26. Farr JN, Xu M, Weivoda MM, Monroe DG, Fraser DG, Onken JL, Negley BA, Sfeir JG, Ogrodnik MB, Hachfeld CM, LeBrasseur NK, Drake MT, Pignolo RJ, Pirtskhalava T, Tchkonia T, Oursler MJ, Kirkland JL, Khosla S. Targeting cellular senescence prevents age-related bone loss in mice. Nat Med. 2017 Sep;23(9):1072-1079. doi: 10.1038/nm.4385. Epub 2017 Aug 21. Erratum in: Nat Med. 2017 Nov 7;23 (11):1384. PMID: 28825716; PMCID: PMC5657592.
  27. Feng C, Yang M, Zhang Y, Lan M, Huang B, Liu H, Zhou Y. Cyclic mechanical tension reinforces DNA damage and activates the p53-p21-Rb pathway to induce premature senescence of nucleus pulposus cells. Int J Mol Med. 2018 Jun;41(6):3316-3326. doi: 10.3892/ijmm.2018.3522. Epub 2018 Feb 28. PMID: 29512682; PMCID: PMC5881642.
  28. Wang F, Zheng C, Wu X. [Research progress of cellular senescence and senescent secretary phenotype in intervertebral disc degeneration]. Zhongguo Xiu Fu Chong Jian Wai Ke Za Zhi. 2012 Dec;26(12):1448-52. Chinese. PMID: 23316633.
  29. Fan J, Yang X, Li J, Shu Z, Dai J, Liu X, Li B, Jia S, Kou X, Yang Y, Chen N. Spermidine coupled with exercise rescues skeletal muscle atrophy from D-gal-induced aging rats through enhanced autophagy and reduced apoptosis via AMPK-FOXO3a signal pathway. Oncotarget. 2017 Mar 14;8(11):17475-17490. doi: 10.18632/oncotarget.15728. PMID: 28407698; PMCID: PMC5392263.
  30. Kritsilis, M., Koutsoudaki, P. N., Evangelou, K., Gorgoulis, V. G., & Papadopoulos, D. (2018). Ageing, Cellular Senescence and Neurodegenerative Disease. International Journal of Molecular Sciences, 19(10), 2937. https://doi.org/10.3390/ijms19102937
  31. Yousefzadeh MJ, Flores RR, Zhu Y, Schmiechen ZC, Brooks RW, Trussoni CE, Cui Y, Angelini L, Lee KA, McGowan SJ, Burrack AL, Wang D, Dong Q, Lu A, Sano T, O’Kelly RD, McGuckian CA, Kato JI, Bank MP, Wade EA, Pillai SPS, Klug J, Ladiges WC, Burd CE, Lewis SE, LaRusso NF, Vo NV, Wang Y, Kelley EE, Huard J, Stromnes IM, Robbins PD, Niedernhofer LJ. An aged immune system drives senescence and ageing of solid organs. Nature. 2021 Jun;594(7861):100-105. doi: 10.1038/s41586-021-03547-7. Epub 2021 May 12. PMID: 33981041; PMCID: PMC8684299.
  32. Luís C, Maduro AT, Pereira P, Mendes JJ, Soares R and Ramalho R (2022) Nutritional senolytics and senomorphics: Implications to immune cells metabolism and aging – from theory to practice. Front. Nutr. 9: 958563.doi: 10.3389/fnut.2022.958563
  33. Riwaldt S, Corydon TJ, Pantalone D, Sahana J, Wise P, Wehland M, Krüger M, Melnik D, Kopp S, Infanger M, Grimm D. Role of Apoptosis in Wound Healing and Apoptosis Alterations in Microgravity. Front Bioeng Biotechnol. 2021 Jun 17;9:679650. doi: 10.3389/fbioe.2021.679650. PMID: 34222218; PMCID: PMC8248797.

Original Version of the Topic

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

Previous Revsion(s) of the Topic

LeAnn Snow, MD, PhD. Cell death/apoptosis. 6/1/2020

Author Disclosures

Sunil K Jain, MD
Nothing to Disclose

Sohil Sheth, BS
Nothing to Disclose