Universality of Senescence

#### **Chapter 1**

## Comparative Senescence and Lifespan

*Hassan M. Heshmati*

#### **Abstract**

The word senescence is derived from the Latin word "senex" (meaning old). In biology, senescence is a process by which a cell ages and permanently stops dividing. Senescence is a natural universal phenomenon affecting all living organisms (e.g., humans, animals, and plants). It is the process of growing old (aging). The underlying mechanisms of senescence and aging at the cellular level are not fully understood. Senescence is a multifactorial process that can be induced by several stimuli including cellular stress, DNA damage, telomere shortening, and oncogene activation. The most popular theory to explain aging is the free radical theory. Senescence plays a role in the development of several age-related chronic diseases in humans (e.g., ischemic heart disease, osteoporosis, and cancer). Lifespan is a biological characteristic of every species. The lifespan of living organisms ranges from few hours (with mayfly) to potential eternity (with jellyfish and hydra). The maximum theoretical lifespan in humans is around 120 years. The lifespan in humans is influenced by multiple factors including genetic, epigenetic, lifestyle, environmental, metabolic, and endocrine factors. There are several ways to potentially extend the lifespan of humans and eventually surpass the maximum theoretical lifespan of 120 years. The tools that can be proposed include lifestyle, reduction of several life-threatening diseases and disabilities, hormonal replacement, antioxidants, autophagy inducers, senolytic drugs, stem cell therapy, and gene therapy.

**Keywords:** senescence, aging, lifespan, humans, animals, plants

#### **1. Introduction**

Senescence is a process by which a cell ages and permanently stops dividing [1]. It is a natural universal phenomenon affecting all living organisms (e.g., humans, animals, and plants). Senescence in cells occurs with the process of growing old (aging). It is a multifactorial process that can be induced by several stimuli including cellular stress, DNA damage, telomere shortening, and oncogene activation.

Lifespan is a biological characteristic of every species. The lifespan of living organisms ranges from few hours (with mayfly) to potential eternity (with jellyfish and hydra). The maximum theoretical lifespan in humans is around 120 years. The lifespan in humans is influenced by multiple factors including genetic, epigenetic, lifestyle, environmental, metabolic, and endocrine factors [2–26].

Lifespan can potentially be extended by mutations or by a variety of interventions in humans, animals, and plants. In humans, interventions such as lifestyle, reduction of several life-threatening diseases and disabilities, hormonal replacement, antioxidants, autophagy inducers, senolytic drugs, stem cell therapy, and gene therapy can potentially help to extend lifespan and eventually surpass 120 years [6–8, 12–15, 17, 20–22, 24–41].

This chapter presents a comparative overview of senescence and lifespan in humans, animals, and plants.

#### **2. History of life on planet Earth**

According to the core accretion theory, planet Earth formed around 4.54 billion years ago (approximately one-third the age of the universe) by accretion from the solar nebula [42]. The initial Earth was a dry planet, without atmosphere and ocean components [43].

The origin of life question is one of the most challenging questions in science. Both ribonucleic acid and peptides played key roles in the emergence of life on Earth [44]. Although the beginning of the presence of life on Earth cannot be determined with accuracy, there is evidence that primitive life with bacteria-like organisms was present around 3.50 billion years ago (**Figure 1**).

#### **Figure 1.**

*Primitive life was likely present on Earth around 3.50 billion years ago. Copyright symkin (Николай Бибик)/ Depositphotos Inc.*

The evolution of species is a complex phenomenon that is supported by several theories. According to Darwin, the natural selection enabled simple life to evolve into complex life over a long period of time (**Figure 2**) [45].

**Figure 2.** *Evolution of humans. Copyright YAYImages (Alex Golke)/Depositphotos Inc.*

### **3. Diversity of life on planet Earth**

Diversity of life refers to the variety of existing living organisms in relation to their species, races, ethnicities, and habitats.

#### **3.1 Species, races, and ethnicities**

There is a variety of species (several million), races, and ethnicities on planet Earth. However, most species, including those living in the ocean, remain to be described [46]. Some species are extremely abundant, while others are moderately common or rare.

#### *3.1.1 Humans*

The historical definition of human races has evolved over more than two centuries. The initial definition of Black, Brown, Red, White, and Yellow races was at the origin of prejudice and racism. These shameful attitudes are still present in our societies.

To encourage diversity and promote uniformity and comparability of data on race and ethnicity, the National Institutes of Health in the USA has defined the following racial and ethnic categories: American Indian or Alaska Native, Asian, Black or African American, Hispanic or Latino, and White. To be comprehensive with this classification, we should also include different combinations of the above races and ethnicities (**Figure 3**).

#### **Figure 3.**

*Diversity of humans. Copyright macrovector (Alejandro Sánchez Blanes)/Depositphotos Inc.*

#### *3.1.2 Animals*

It is estimated that there are over 7 million animal species, but most have not been described (**Figure 4**). With approximately 1,000,000 described species, insects represent about 55% of all known species.

The basic animal classes include invertebrates, fish, amphibians, reptiles, birds, and mammals. Within each animal species, there are several breeds. For dogs, for example, more than 300 breeds have been described.

**Figure 4.** *Diversity of animal species. Copyright Jim\_Filim (Iakov Filimonov)/Depositphotos Inc.*

#### *3.1.3 Plants*

There are close to 400,000 species of plants. The large majority of plants are vascular and flowering plants (**Figure 5**).

**Figure 5.** *Diversity of plant species. Copyright interactimages (Matthew Cole)/Depositphotos Inc.*

#### **3.2 Habitats**

There are two main types of habitats for the living organisms: terrestrial (e.g., regular land, grassland, forest, desert, mountain, and polar region) and aquatic (freshwater, marine, and coastal region). Based on their habitat, living organisms can be exposed to a variety of air, sunlight, temperature, humidity, and noise (**Figure 6**).

**Figure 6.** *Organisms living in the water. Copyright Vlad61 (Владимир Голубев)/Depositphotos Inc.*

### **4. Senescence and aging**

The word senescence is derived from the Latin word "senex" (meaning old). In biology, senescence is a process by which a cell ages and permanently stops dividing. In addition to exiting the cell cycle, senescent cells undergo other phenotypic alterations including metabolic reprogramming, chromatin rearrangement, and autophagy modulation [1]. Senescence is a natural universal phenomenon affecting all living organisms (e.g., humans, animals, and plants). However, there is a wide range of diversity in the pattern of senescence across species. Senescence is the process of growing old (aging) with a progressive deterioration of the cell and organ functioning. Senescence is associated with a decrease in fertility and/or an increase in mortality.

#### **4.1 Mechanisms**

The underlying mechanisms of senescence and aging at the cellular level are not fully understood. Senescence is a multifactorial process that can be induced by several stimuli including cellular stress, DNA damage, telomere shortening, and oncogene activation. The most popular theory to explain aging is the free radical theory [47]. According to this theory, continuous, unrepaired oxidative damage of macromolecules constitutes the molecular basis of aging.

#### *4.1.1 Humans*

Human senescence and aging result from accumulation over time of genetic, molecular, and cellular damages.

Aging is associated with a gradual, time-dependent, and heterogeneous decline of physiological functions ultimately leading to death (**Figure 7**). The human body goes through multiple changes including endothelial pro-atherosclerotic changes, an overall decrease in the size of organs, ovarian atrophy, osteopenia, sarcopenia, skin atrophy, and adipose tissue enlargement (non-exhaustive list) [7, 10, 12, 26]. Some of these changes play a role in the development of several age-related chronic diseases (e.g., ischemic heart disease, osteoporosis, and cancer) responsible for increased mortality. Senescence is emerging as a therapeutic target for several diseases.

**Figure 7.** *Evolution of humans with aging. Copyright cherstva (Olena Cherstva)/Depositphotos Inc.*

#### *4.1.2 Animals*

Senescence and aging are also present in animals and influenced by multiple factors including genetic and environmental factors [48]. The rate and intensity of aging vary considerably among animals. Interestingly, some animals do not exhibit clear evidence of biological aging (negligible senescence) and have superior resistance to age-related diseases. These animals include ocean quahog clam, Greenland shark, Aldabra giant tortoise, rougheye rockfish, freshwater pearl mussel, and naked mole-rat (non-exhaustive list). At least two animals, jellyfish (*Turritopsis dohrnii*) and hydra, are considered potentially immortal [49].

#### *4.1.3 Plants*

Senescence and aging in plants are associated with a complex deterioration of cellular metabolism that includes loss of chlorophyll, carotenoids, and proteins, and an increase in lipid peroxidation and membrane permeability, leading to a decline in photosynthesis. Multiple factors including phytohormones, sunlight, temperature, and water play a role in plant senescence [50].

#### **5. Lifespan**

Lifespan is a biological characteristic of every species. It is determined by a complex interaction between genetic and environmental factors. The lifespan of living organisms ranges from few hours (animals) to few thousand years (animals and plants) or to eternity (animals). Phenotypic plasticity can affect the long lifespan of both animals and plants [48].

#### **5.1 Lifespan by species**

#### *5.1.1 Humans*

The lifespan in humans is influenced by multiple factors including genetic, epigenetic, lifestyle, environmental, metabolic, and endocrine factors [2–26].

The maximum theoretical lifespan in humans is around 120 years. Very few individuals reach this theoretical age since several events can impact lifespan (e.g., diseases, suicide, accident, and war).

Centenarians are subjects living 100 years or older. They represent a model of successful aging [9, 31, 51, 52]. Semi-supercentenarians are those who reach an age of 105–109 years (**Figure 8**). A very small fraction of centenarians (up to 0.5%) will live 110 years or older (supercentenarians) [5, 52]. The oldest supercentenarian with well-documented age was Jeanne Louise Calment (1875–1997) from Arles (France) who lived 122 years. The second oldest supercentenarian was Sarah DeRemer Knauss (1880–1999) from Hollywood, Pennsylvania (USA) who lived 119 years.

According to United Nations estimates, in 2020, the number of centenarians in the world was approximately 573,000 (mainly from the USA). This number could reach approximately 3,676,000 by 2050 (mainly from China).

#### **Figure 8.**

*A semi-supercentenarian Chinese woman (105 years old) and her great granddaughter. Copyright ChinaImages (IMAGINECHINA LIMITED)/Depositphotos Inc.*

#### *5.1.2 Animals*

The lifespan in animals is between few hours to potential eternity. The shortest lifespan is seen with mayfly (1 day). Aside from jellyfish (*Turritopsis dohrnii*) (**Figure 9**) and hydra which are considered potentially immortal animals, the longest lifespan has been observed with glass sponge (around 10,000 years) (**Table 1**) [49].

#### **Figure 9.**

*Jellyfish (Turritopsis dohrnii) is considered a potentially immortal animal. Copyright Winston (Sergey Belov)/ Depositphotos Inc.*


*Comparative Senescence and Lifespan DOI: http://dx.doi.org/10.5772/intechopen.105137*


#### **Table 1.**

*Lifespan (average or record) in animals ranked by descending order of duration (non-exhaustive list).*

#### *5.1.3 Plants*

The lifespan in plants ranges from few weeks (in annuals) to few thousand years (in trees). Bristlecone pine (*Pinus longaeva*), a tree found in the higher mountains of California (USA), is among the plants with the longest lifespan (around 5,000 years) (**Figure 10**).

#### **Figure 10.**

*Bristlecone pine (Pinus longaeva) can live around 5,000 years. Copyright mkopka (Melissa Kopka)/ Depositphotos Inc.*

#### **5.2 Evolution of lifespan**

The important increase in human lifespan over the past 100 years is one of the greatest achievements of humanity [53]. The evolution of human lifespan over time is reported in **Table 2**.


#### **Table 2.**

*Evolution of average lifespan in humans throughout the history of mankind.*

#### **5.3 Interventions to extend lifespan**

Although lifespan is a biological characteristic of every species, it can be modified by mutations or by a variety of interventions in humans, animals, and plants.

Extending lifespan while keeping health and vitality has always been a dream for mankind. The "successful aging" is aging without any disabilities and severe diseases (**Figure 11**) [27, 53].

**Figure 11.** *Healthy old couple. Copyright nicoletaionescu (Nicoleta Ionescu)/Depositphotos Inc.*

There are several ways to potentially extend the lifespan of humans and eventually surpass the maximum theoretical lifespan of 120 years. The tools that can be proposed include lifestyle, reduction of several life-threatening diseases and disabilities, hormonal replacement, antioxidants, autophagy inducers, senolytic drugs, stem cell therapy, and gene therapy (**Table 3**) (**Figure 12**) [6–8, 12–15, 17, 20–22, 24–41].

Clinical trials using anti-senescent therapies are in progress. Results from early pilot studies suggest that senolytic drugs can decrease senescent cells, reduce inflammation, and alleviate frailty. Stem cell therapy represents a new emerging era in medicine that has the potential to delay the aging process and, therefore, extend lifespan, by better treating life-threatening diseases that impact lifespan. Genetic interventions, although promising, may be difficult to implement in humans without the knowledge of all the potential health consequences during entire life.

*Comparative Senescence and Lifespan DOI: http://dx.doi.org/10.5772/intechopen.105137*


#### **Table 3.**

*Tools proposed for the potential extension of the lifespan in humans (non-exhaustive list).*

#### **Figure 12.**

*Regular exercise can be very beneficial for the extension of lifespan. Copyright kornetka (Svetlana Ivanova)/ Depositphotos Inc.*

#### **6. Conclusions**

Senescence is a process by which a cell ages and permanently stops dividing. It is a natural universal phenomenon affecting all living organisms (e.g., humans, animals, and plants). Senescence is the process of growing old (aging). It can be induced by several stimuli including cellular stress, DNA damage, telomere shortening, and oncogene activation. The most popular theory to explain aging is the free radical theory.

Lifespan is a biological characteristic of every species. The lifespan of living organisms ranges from few hours (with mayfly) to potential eternity (with jellyfish and hydra). The maximum theoretical lifespan in humans is around 120 years. The lifespan in humans is influenced by multiple factors including genetic, epigenetic, lifestyle, environmental, metabolic, and endocrine factors. The lifespan in animals is between few hours to potential eternity. The lifespan in plants ranges from few weeks to few thousand years.

There are tools that can potentially extend the lifespan of humans and eventually surpass 120 years. They include lifestyle, reduction of several life-threatening diseases and disabilities, hormonal replacement, antioxidants, autophagy inducers, senolytic drugs, stem cell therapy, and gene therapy.

### **Conflict of interest**

The author declares no conflict of interest.

### **Author details**

Hassan M. Heshmati Endocrinology Metabolism Consulting, LLC, Anthem, AZ, USA

\*Address all correspondence to: hassanheshmati@yahoo.com

© 2022 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

### **References**

[1] Herranz N, Gil J. Mechanisms and functions of cellular senescence. The Journal of Clinical Investigation. 2018;**128**:1238-1246. DOI: 10.1172/ JCI95148

[2] Sebastiani P, Perls TT. The genetics of extreme longevity: Lessons from the New England Centenarian Study. Frontiers in Genetics. 2012;**3**:277. DOI: 10.3389/ fgene.2012.00277

[3] Budovsky A, Craig T, Wang J, et al. LongevityMap: A database of human genetic variants associated with longevity. Trends in Genetics. 2013;**29**:559-560. DOI: 10.1016/j. tig.2013.08.003

[4] Shadyab AH, LaCroix AZ. Genetic factors associated with longevity: A review of recent findings. Ageing Research Reviews. 2015;**19**:1-7. DOI: 10.1016/j.arr.2014.10.005

[5] Horvath S, Pirazzini C, Bacalini MG, et al. Decreased epigenetic age of PBMCs from Italian semi-supercentenarians and their offspring. Aging. 2015;**7**:1159-1170. DOI: 10.18632/aging.100861

[6] Govindaraju D, Atzmon G, Barzilai N. Genetics, lifestyle and longevity: Lessons from centenarians. Applied & Translational Genomics. 2015;**4**:23-32. DOI: 10.1016/j.atg.2015.01.001

[7] Sgarbieri VC, Pacheco MTB. Healthy human aging: Intrinsic and environmental factors. Brazilian Journal of Food Technology. 2017;**20**:e2017007. DOI: 10.1590/1981-6723.00717

[8] Puca AA, Spinelli C, Accardi G, Villa F, Caruso C. Centenarians as a model to discover genetic and epigenetic signatures of healthy ageing. Mechanisms of Ageing

and Development. 2018;**174**:95-102. DOI: 10.1016/j.mad.2017.10.004

[9] Borras C, Ingles M, Mas-Bargues C, et al. Centenarians: An excellent example of resilience for successful ageing. Mechanisms of Ageing and Development. 2020;**186**:111199. DOI: 10.1016/j.mad.2019.111199

[10] Bektas A, Schurman SH, Sen R, Ferrucci L. Aging, inflammation and the environment. Experimental Gerontology. 2018;**105**:10-18. DOI: 10.1016/j. exger.2017.12.015

[11] Barzilai N, Gabriely I. Genetic studies reveal the role of the endocrine and metabolic systems in aging. The Journal of Clinical Endocrinology & Metabolism. 2010;**95**:4493-4500. DOI: 10.1210/ jc.2010-0859

[12] Barzilai N, Huffman DM, Muzumdar RH, Bartke A. The critical role of metabolic pathways in aging. Diabetes. 2012;**61**:1315-1322. DOI: 10.2337/db11-1300

[13] López-Otín C, Galluzzi L, Freije JMP, Madeo F, Kroemer G. Metabolic control of longevity. Cell. 2016;**166**:802-821. DOI: 10.1016/j.cell.2016.07.031

[14] Barbosa MC, Grosso RA, Fader CM. Hallmarks of aging: An autophagic perspective. Frontiers in Endocrinology. 2019;**9**:790. DOI: 10.3389/fendo. 2018.00790

[15] Allard JB, Duan C. Comparative endocrinology of aging and longevity regulation. Frontiers in Endocrinology. 2011;**2**:75. DOI: 10.3389/fendo.2011.00075

[16] Chen TT, Maevsky EI, Uchitel ML. Maintenance of homeostasis in the aging hypothalamus: The central and peripheral roles of succinate. Frontiers in Endocrinology. 2015;**6**:7. DOI: 10.3389/ fendo.2015.00007

[17] Diamanti-Kandarakis E, Dattilo M, Macut D, et al. Aging and anti-aging: A combo-endocrinology overview. European Journal of Endocrinology. 2017;**176**:R283-R308. DOI: 10.1530/ EJE-16-1061

[18] Colon G, Saccon T, Schneider A, et al. The enigmatic role of growth hormone in age-related diseases, cognition, and longevity. GeroScience. 2019;**41**:759-774. DOI: 10.1007/ s11357-019-00096-w

[19] Bartke A. Growth hormone and aging. Reviews in Endocrine and Metabolic Disorders. 2021;**22**:71-80. DOI: 10.1007/s11154-020-09593-2

[20] Bowers J, Terrien J, Clerget-Froidevaux MS, et al. Thyroid hormone signaling and homeostasis during aging. Endocrine Reviews. 2013;**34**:556-589. DOI: 10.1210/ er.2012-1056

[21] Longo M, Bellastella G, Maiorino MI, Meier JJ, Esposito K, Giugliano D. Diabetes and aging: From treatment goals to pharmacologic therapy. Frontiers in Endocrinology. 2019;**10**:45. DOI: 10.3389/ fendo.2019.00045

[22] Salpeter SR, Cheng J, Thabane L, Buckley NS, Salpeter EE. Bayesian meta-analysis of hormone therapy and mortality in younger postmenopausal women. The American Journal of Medicine. 2009;**122**:1016-1022. DOI: 10.1016/j.amjmed.2009.05.021

[23] Araujo AB, Dixon JM, Suarez EA, Hassan Murad M, Guey LT, Wittert GA. Endogenous testosterone and mortality in men: A systematic review and

meta-analysis. The Journal of Clinical Endocrinology & Metabolism. 2011;**96**:3007-3019. DOI: 10.1210/ jc.2011-1137

[24] Lorenzini A. How much should we weigh for a long and healthy life span? The need to reconcile caloric restriction versus longevity with body mass index versus mortality data. Frontiers in Endocrinology. 2014;**5**:121. DOI: 10.3389/ fendo.2014.00121

[25] The Global BMI Mortality Collaboration. Body-mass index and all-cause mortality: Individualparticipant-data meta-analysis of 239 prospective studies in four continents. Lancet. 2016;**388**:776-786. DOI: 10.1016/ S0140-6736(16)30175-1

[26] Mancuso P, Bouchard B. The impact of aging on adipose function and adipokine synthesis. Frontiers in Endocrinology. 2019;**10**:137. DOI: 10.3389/fendo.2019.00137

[27] Beard JR, Officer A, Araujo de Carvalho I, et al. The world report on ageing and health: A policy framework for healthy ageing. Lancet. 2016;**387**:2145-2154. DOI: 10.1016/ S0140-6736(15)00516-4

[28] Barzilai N, Cuervo AM, Austad S. Aging as a biological target for prevention and therapy. Journal of the American Medical Association. 2018;**320**:1321-1322. DOI: 10.1001/ jama.2018.9562

[29] Shetty AK, Kodali M, Upadhya R, Madhu LN. Emerging anti-aging strategies – Scientific basis and efficacy. Aging and Disease. 2018;**9**:1165-1184. DOI: 10.14336/AD.2018.1026

[30] Tchkonia T, Kirkland JL. Aging, cell senescence, and chronic disease. Emerging therapeutic strategies.

*Comparative Senescence and Lifespan DOI: http://dx.doi.org/10.5772/intechopen.105137*

Journal of the American Medical Association. 2018;**320**:1319-1320. DOI: 10.1001/jama.2018.12440

[31] Heshmati HM. The centenarians: An emerging population. In: Amornyotin S, editor. Update in Geriatrics. London: IntechOpen; 2021. pp. 3-23. DOI: 10.5772/intechopen.96327

[32] Abbasi J. Can a diet that mimics fasting turn back the clock? Journal of the American Medical Association. 2017;**318**:227-229. DOI: 10.1001/ jama.2017.6648

[33] Pereira da Silva A, Valente A, Chaves C, et al. Characterization of Portuguese centenarian eating habits, nutritional biomarkers, and cardiovascular risk: A case control study. Oxidative Medicine and Cellular Longevity. 2018;**2018**:5296168. DOI: 10.1155/2018/5296168

[34] Castillo-Garzón MJ, Ruiz JR, Ortega FB, Gutiérrez ÁG. Anti-aging therapy through fitness enhancement. Clinical Interventions in Aging. 2006;**1**:213-220. DOI: 10.2147/ ciia.2006.1.3.213

[35] Weiss EP, Villareal DT, Fontana L, Han DH, Holloszy JO. Dehydroepiandrosterone (DHEA) replacement decreases insulin resistance and lowers inflammatory cytokines in aging humans. Aging. 2011;**3**:533-542. DOI: 10.18632/aging.100327

[36] Levine B, Packer M, Codogno P. Development of autophagy inducers in clinical medicine. The Journal of Clinical Investigation. 2015;**125**:14-24. DOI: 10.1172/JCI73938

[37] Myrianthopoulos V. The emerging field of senotherapeutic drugs. Future Medicinal Chemistry. 2018;**10**:2369-2372. DOI: 10.4155/fmc-2018-0234

[38] Kirkland JL, Tchkonia T. Senolytic drugs: From discovery to translation. Journal of Internal Medicine. 2020;**288**:518-536. DOI: 1111/joim.13141

[39] Ullah M, Sun Z. Stem cells and anti-aging genes: Double-edged sword-do the same job of life extension. Stem Cell Research & Therapy. 2018;**9**:3. DOI: 10.1186/s13287-017-0746-4

[40] Schulman IH, Balkan W, Hare JM. Mesenchymal stem cell therapy for aging frailty. Frontiers in Nutrition. 2018;**5**:108. DOI: 10.3389/fnut.2018.00108

[41] Vaiserman A, De Falco E, Koliada A, Maslova O, Balistreri CR. Anti-ageing gene therapy: Not so far away? Ageing Research Reviews. 2019;**56**:100977. DOI: 10.1016/j.arr.2019.100977

[42] Co'Neill HS. The origin of the moon and the early history of the earth – A chemical model. Part 2: The earth. Geochimica et Cosmochimica Acta. 1991;**55**:1159-1172. DOI: 10.1016/ 0016-7037(91)90169-6

[43] Maruyama S, Ebisuzaki T. Origin of the Earth: A proposal of new model called ABEL. Geoscience Frontiers. 2017;**8**:253-274. DOI: 10.1016/j. gsf.2016.10.005

[44] Saad NY. A ribonucleopeptide world at the origin of life. Journal of Systematics and Evolution. 2018;**56**:1-13. DOI: 10.1111/jse.12287

[45] Avise JC, Ayala FJ. In the light of evolution III: Two centuries of Darwin. PNAS. 2009;**106**(Suppl 1):9933-9938. DOI: 10.1073/pnas.0903381106

[46] Mora C, Tittensor DP, Adl S, Simpson AGB, Worm B. How many species are there on Earth and in the ocean? PLOS Biology. 2011;**9**:e1001127. DOI: 10.1371/journal.pbio.1001127

[47] Harman D. Aging: Origin and evolution of the free radical theory of aging: A brief personal history, 1954- 2009. Biogerontology. 2009;**10**:773-781. DOI: 10.1007/s10522-009-9234-2

[48] Borges RM. Phenotypic plasticity and longevity in plants and animals: Cause and effect? Journal of Biosciences. 2009;**34**:605-611. DOI: 10.1007/ s12038-009-0078-3

[49] Petralia RS, Mattson MP, Yao PJ. Aging and longevity in the simplest animals and the quest for immortality. Ageing Research Reviews. 2014;**16**: 66-82. DOI: 10.1016/j.arr.2014.05.003

[50] Jyothsna P, Murthy SDS. A review on effect of senescence in plants and role of phytohormones in delaying senescence. International Journal of Plant, Animal and Environmental Sciences. 2016;**6**:152-161

[51] Salvioli S, Capri M, Bucci L, et al. Why do centenarians escape or postpone cancer? The role of IGF-1, inflammation and p53. Cancer Immunology, Immunotherapy. 2009;**58**:1909-1917. DOI: 10.1007/s00262-008-0639-6

[52] Andersen SL, Sebastiani P, Dworkis DA, Feldman L, Perls TT. Health span approximates life span among many supercentenarians: Compression of morbidity at the approximate limit of life span. The Journals of Gerontology, Series A: Biological Sciences and Medical Sciences. 2012;**67A**:395-405. DOI: 10.1093/gerona/glr223

[53] Olshansky SJ. From lifespan to healthspan. Journal of the American Medical Association. 2018;**320**:1323- 1324. DOI: 10.1001/jama.2018.12621

Section 2
