Octogenarians, Nonagenarians, & Centenarians

[Michael Scally MD]

Centenarians: An Excellent Example of Resilience for Successful Ageing

Highlights
· Centenarians maintain intrinsic capacity longer than individuals who display ordinary aging.
· Resilience is a determinant of health, and centenarians maintain it longer.
· Centenarians have specific genetic features.

Centenarians are remarkable not only because of their prolonged life, but also because they compress morbidity until the very last moments of their lives, thus being proposed as a model of successful, extraordinary ageing.

From the medical viewpoint, centenarians do not escape the physiological decline or the age-related diseases or syndromes (i.e. frailty), but the rate of such processes is slow enough to be counterbalanced by their increased intrinsic capacity to respond to minor stresses of daily life (i.e. resilience).

These new concepts are reviewed in this paper. Allostatic stresses lead to a chronic low-grade inflammation that has led to the proposal of the "inflammaging" theory of ageing and frailty. The biology of centenarians, described in this review, provides us with clues for intervention to promote healthy ageing in the general population.

One of the major reasons for this healthy ageing has to do with the genetic signature that is specific for centenarians and certainly different from octogenarians who do not enjoy the extraordinary qualities of centenarians.

Borras C, Ingles M, Mas-Bargues C, et al. Centenarians: An excellent example of resilience for successful ageing [published online ahead of print, 2019 Dec 31]. Mech Ageing Dev. 2019;111199. Centenarians: An excellent example of resilience for successful ageing - ScienceDirect

 

[Michael Scally MD]

[OA] Lifestyle vs. Pharmacological Interventions for Healthy Aging

The fountain of youth, the elixir of life, the Philosopher’s stone, or an analogous mythical object to remedy the scourges of aging, has been sought after throughout the history of humankind, up to the present day. In modern times, inventing a drug that prevents the aging-linked decline in organ function, expands the years of life spent in good health, or even increases lifespan promises fame and fortune for the discoverer.

Vitamins, anti-oxidants, resveratrol and other alleged sirtuin activators, caloric restriction, nicotinamide adenine dinucleotide (NAD+) and its biosynthetic precursors, young blood and growth and differentiation factor 11 (GDF 11), senolytics, rapamycin and rapalogs, metformin as well as numerous other compounds and treatments all were (or still are) considered as the magic bullet for “anti-aging” effects in the last couple of years.

However, for most, if not all of them, preclinical results in animal models were difficult to translate to humans, unexpected adverse effects in animals or humans were reported, and/or clinical trials showing any efficacy in healthy young and old individuals are still elusive. Importantly, aging per se is not recognized as a disease, and so-called “anti-aging” effects are often difficult to disentangle from disease prevention. …

These observations emphasize the complexity of cellular and organismal adaptation to exercise and aging that impedes the development of pharmacological monotherapies. Thus, the next years will not only reveal whether promising preclinical results with such compounds will stand the test of time in human trials, but also indicate the compatibility with other interventions and treatments.

However, as long as data about clinical efficacy and safety of exercise “mimetics” and “anti-aging” drugs are missing (and probably even beyond that), lifestyle-based interventions remain the mainstay approach to minimize the risk for diseases, reduce morbidity and mortality and most importantly, improve healthspan in aging. The old adage “use it or lose it” should thus serve as a reminder that regular physical activity is directly and strongly linked to health in the young and the elderly.

Furrer R, Handschin C. Lifestyle vs. pharmacological interventions for healthy aging [published online ahead of print, 2020 Jan 10]. Aging (Albany NY). 2020;5–7. https://doi.org/10.18632/aging.102741

 

[Michael Scally MD]

Exercise in People Over 85

Societies are progressively ageing, and people aged ≥85 years, who are projected to more than triple in number by 2050, represent the most rapidly expanding population group.1 How to preserve health and function at an advanced age is an increasingly important challenge for healthcare professionals and the public.

According to the World Health Organization, healthy ageing is largely determined by the ability to maintain both mental and physical capacity––together known as intrinsic capacity.2 No drugs exist to improve physical capacity in the oldest people, and none is likely to be developed in the foreseeable future. Evidence is growing, however, to support interventions based on physical exercise.

…

In an era of complex regenerative medicine, when some scientists are even considering the expansion of human life well beyond its known limits, we must not forget the simple and important message: exercise is not just for children and younger adults, people of advanced age can adapt to exercise and deserve to benefit from it.

Generalists should advise all patients, regardless of age, to be as active as possible. Medical schools should teach students that skeletal muscle remains a plastic, adaptable tissue throughout the human lifespan. It is never too late––and you are never too old––to contract muscles.

Izquierdo M, Morley JE, Lucia A. Exercise in people over 85. BMJ. 2020;368:m402. Published 2020 Feb 5. https://www.bmj.com/content/368/bmj.m402

 

[Michael Scally MD]

[OA] The Phenotypic Characterization of the Cammalleri Sisters, an Example of Exceptional Longevity

This article shows demographic, clinical, anamnestic, cognitive, and functional data as well as biochemical, genetic, and epigenetic parameters of two exceptional siblings: Diega (supercentenarian) and Filippa (semisupercentenarian) Cammalleri.

The purpose of this study is to provide new insights into the extreme phenotypes represented by semisupercentenarians and supercentenarians. Different studies have been published on supercentenarians, but to the best of our knowledge, this is the only concerning two sisters and the most detailed from a phenotypic point of view.

Our findings agree with the suggestion that supercentenarians have an increasing relative resistance to age-related diseases, approximating the limits of the functional human reserve to address successfully the acute causes of death. More interestingly, our data agree with, and extend, the suggestion that inflammation and oxidative stress predict centenarian mortality.

Accardi G, Aiello A, Aprile S, et al. The Phenotypic Characterization of the Cammalleri Sisters, an Example of Exceptional Longevity. Rejuvenation research 2020. https://doi.org/10.1089/rej.2019.2299

 

[Michael Scally MD]

The Quest To Slow Ageing Through Drug Discovery

Although death is inevitable, individuals have long sought to alter the course of the ageing process. Indeed, ageing has proved to be modifiable; by intervening in biological systems, such as nutrient sensing, cellular senescence, the systemic environment and the gut microbiome, phenotypes of ageing can be slowed sufficiently to mitigate age-related functional decline. These interventions can also delay the onset of many disabling, chronic diseases, including cancer, cardiovascular disease and neurodegeneration, in animal models.

Here, we examine the most promising interventions to slow ageing and group them into two tiers based on the robustness of the preclinical, and some clinical, results, in which the top tier includes rapamycin, senolytics, metformin, acarbose, spermidine, NAD+ enhancers and lithium. We then focus on the potential of the interventions and the feasibility of conducting clinical trials with these agents, with the overall aim of maintaining health for longer before the end of life.

Partridge, L., Fuentealba, M. & Kennedy, B.K. The quest to slow ageing through drug discovery. Nat Rev Drug Discov (2020). https://doi.org/10.1038/s41573-020-0067-7

 

[Michael Scally MD]

Genetics of Extreme Human Longevity to Guide Drug Discovery for Healthy Ageing

Ageing is the greatest risk factor for most common chronic human diseases, and it therefore is a logical target for developing interventions to prevent, mitigate or reverse multiple age-related morbidities. Over the past two decades, genetic and pharmacologic interventions targeting conserved pathways of growth and metabolism have consistently led to substantial extension of the lifespan and healthspan in model organisms as diverse as nematodes, flies and mice.

Recent genetic analysis of long-lived individuals is revealing common and rare variants enriched in these same conserved pathways that significantly correlate with longevity. In this Perspective, we summarize recent insights into the genetics of extreme human longevity and propose the use of this rare phenotype to identify genetic variants as molecular targets for gaining insight into the physiology of healthy ageing and the development of new therapies to extend the human healthspan.

Zhang ZD, Milman S, Lin JR, et al. Genetics of extreme human longevity to guide drug discovery for healthy ageing [published online ahead of print, 2020 Jul 27]. Nat Metab. 2020;10.1038/s42255-020-0247-0. doi:10.1038/s42255-020-0247-0 Genetics of extreme human longevity to guide drug discovery for healthy ageing | Nature Metabolism

 

[ToastEater]

For us non scientists can we get a summary?

 

[Michael Scally MD]

 

[Michael Scally MD]

Achieving Healthy Human Longevity: A Global Grand Challenge

Over the past century, major advances in medicine, public health, and socioeconomic development have led to unprecedented extensions of life expectancy worldwide. Coupled with declining mortality and fertility rates, a major demographic transition has emerged globally. In 2018, for the first time, the number of people over the age of 64 surpassed the number of children younger than 5. By 2050, nearly 20% of the world’s population will be over the age of 65.

Global population aging presents both new opportunities and challenges. The COVID-19 pandemic has challenged recent advances in science and medicine and underscored the vulnerability of older populations to emerging diseases, alongside existing age-associated susceptibilities to noncommunicable diseases. Without innovation and adaptation, societal aging is poised to strain health care systems, economies, and social structures worldwide. Health care costs will rise and public benefit programs will become strained or depleted. As families have become smaller and more disperse, limited support within the family may be available.

Yet, these and other looming stressors are not inevitable and could be mitigated, if not avoided, by accelerating biomedical and technological advancements, as well as socioeconomic infrastructures and policies to keep people healthier throughout their lives. By extending the health span, defined as the healthy years of life, societies can benefit from the tremendous social and economic opportunities that come with an active and vibrant older population.

Dzau VJ, Finkelman EM, Balatbat CA, Verdin EM, Pettigrew RI. Achieving healthy human longevity: A global grand challenge. Sci Transl Med. 2020 Oct 21;12(566):eabd3816. doi: 10.1126/scitranslmed.abd3816. PMID: 33087500. https://stm.sciencemag.org/content/12/566/eabd3816

 

[Michael Scally MD]

New Horizons: Novel Approaches to Enhance Healthspan Through Targeting Cellular Senescence and Related Aging Mechanisms

The elderly population is increasing faster than other segments of the population throughout the world. Age is the leading predictor for most chronic diseases and disorders, multimorbidity, geriatric syndromes, and impaired ability to recover from accidents or illnesses. Enhancing the duration of health and independence, termed healthspan, would be more desirable than extending lifespan merely by prolonging the period of morbidity toward the end of life.

The geroscience hypothesis posits that healthspan can be extended by targeting fundamental aging mechanisms, rather than attempting to address each age-related disease one at a time, only so the afflicted individual survives disabled and dies shortly afterward of another age-related disease.

These fundamental aging mechanisms include, among others, chronic inflammation, fibrosis, stem cell/ progenitor dysfunction, DNA damage, epigenetic changes, metabolic shifts, destructive metabolite generation, mitochondrial dysfunction, misfolded or aggregated protein accumulation, and cellular senescence.

These processes appear to be tightly interlinked, as targeting any one appears to affect many of the rest, underlying our Unitary Theory of Fundamental Aging Mechanisms. Interventions targeting many fundamental aging processes are being developed, including dietary manipulations, metformin, mTOR (mechanistic target of rapamycin) inhibitors, and senolytics, which are in early human trials. These interventions could lead to greater healthspan benefits than treating age-related diseases one at a time.

To illustrate these points, we focus on cellular senescence and therapies in development to target senescent cells. Combining interventions targeting aging mechanisms with disease-specific drugs could result in more than additive benefits for currently difficult-to-treat or intractable diseases. More research attention needs to be devoted to targeting fundamental aging processes.

Tchkonia T, Palmer AK, Kirkland JL. New Horizons: Novel Approaches to Enhance Healthspan Through Targeting Cellular Senescence and Related Aging Mechanisms. J Clin Endocrinol Metab. 2020 Nov 6:dgaa728. doi: 10.1210/clinem/dgaa728. Epub ahead of print. PMID: 33155651. New Horizons: Novel Approaches to Enhance Healthspan Through Targeting Cellular Senescence and Related Aging Mechanisms

 

[Michael Scally MD]

[OA] Optimism Is Associated with Exceptional Longevity

Most research on exceptional longevity has investigated biomedical factors associated with survival, but recent work suggests nonbiological factors are also important. Thus, we tested whether higher optimism was associated with longer life span and greater likelihood of exceptional longevity.

Data are from 2 cohorts, women from the Nurses' Health Study (NHS) and men from the Veterans Affairs Normative Aging Study (NAS), with follow-up of 10 y (2004 to 2014) and 30 y (1986 to 2016), respectively. Optimism was assessed using the Life Orientation Test-Revised in NHS and the Revised Optimism-Pessimism Scale from the Minnesota Multiphasic Personality Inventory-2 in NAS.

Exceptional longevity was defined as survival to age 85 or older. Primary analyses used accelerated failure time models to assess differences in life span associated with optimism; models adjusted for demographic confounders and health conditions, and subsequently considered the role of health behaviors. Further analyses used logistic regression to evaluate the likelihood of exceptional longevity.

In both sexes, we found a dose-dependent association of higher optimism levels at baseline with increased longevity (P trend < 0.01). For example, adjusting for demographics and health conditions, women in the highest versus lowest optimism quartile had 14.9% (95% confidence interval, 11.9 to 18.0) longer life span. Findings were similar in men. Participants with highest versus lowest optimism levels had 1.5 (women) and 1.7 (men) greater odds of surviving to age 85; these relationships were maintained after adjusting for health behaviors.

Given work indicating optimism is modifiable, these findings suggest optimism may provide a valuable target to test for strategies to promote longevity.

Lee LO, James P, Zevon ES, et al. Optimism is associated with exceptional longevity in 2 epidemiologic cohorts of men and women. Proc Natl Acad Sci U S A. 2019 Sep 10;116(37):18357-18362. doi: 10.1073/pnas.1900712116. Epub 2019 Aug 26. PMID: 31451635; PMCID: PMC6744861. Optimism is associated with exceptional longevity in 2 epidemiologic cohorts of men and women

 

[Michael Scally MD]

#148 – Richard Miller, M.D., Ph.D.: The gold standard for testing longevity drugs: the Interventions Testing Program
#148 - Richard Miller, M.D., Ph.D.: The gold standard for testing longevity drugs: the Interventions Testing Program - Peter Attia

Richard Miller is a professor of pathology and the Director of the Center for Aging Research at the University of Michigan. He is one of the architects of the NIA-funded Interventions Testing Programs (ITPs) animal study test protocol.

In this episode, Rich goes through the results of the long list of molecules tested by the ITP—including rapamycin, metformin, nicotinamide riboside, an SGLT-2 inhibitor called canagliflozin, and more. Many of the discussed outcomes have had surprising outcomes—both positive and negative findings.


We discuss:

Rich’s interest in aging, and how Hayflick’s hypothesis skewed aging research (3:45);

Dispelling the myth that aging can’t be slowed (15:00);

The Interventions Testing Program—A scientific framework for testing whether drugs extend lifespan in mice (29:00);

Testing aspirin in the first ITP cohort (38:45);

Rapamycin: results from ITP studies, dosing considerations, and what it tells us about early- vs. late-life interventions (44:45);

Acarbose as a potential longevity agent by virtue of its ability to block peak glucose levels (1:07:15);

Resveratrol: why it received so much attention as a longevity agent, and the takeaways from the negative results of the ITP study (1:15:45);

The value in negative findings: ITP studies of green tea extract, methylene blue, curcumin, and more (1:24:15);

17α-Estradiol: lifespan effects in male mice, and sex-specific effects of different interventions (1:27:00);

Testing ursolic acid and hydrogen sulfide: rationale and preliminary results (1:33:15);

Canagliflozin (an SGLT2 inhibitor): exploring the impressive lifespan results in male mice (1:35:45);

The failure of metformin: reconciling negative results of the ITP with data in human studies (1:42:30);

Nicotinamide riboside: insights from the negative results of the ITP study (1:48:45);

The three most important takeaways from the ITP studies (1:55:30);

Philosophies on studying the aging process: best model organisms, when to start interventions, which questions to ask, and more (1:59:30);

Seven reasons why pigs can’t fly (2:08:00); and

More.

 

[Michael Scally MD]

How Much Exercise Do You Need for Better Heart Health?
How Much Exercise Do You Need for Better Heart Health?

If you want a healthy heart, the more you exercise, the better, according to an encouraging new study of the links between physical activity and cardiovascular disease. It finds that people who often exercise and stay active are much less likely to develop heart disease than people who rarely move, whether that exercise consists of a few minutes a day of jogging or multiple hours a week of walking.

The large-scale study, which relied on objective data about exercise from more than 90,000 adults, bolsters the growing evidence that almost any amount of physical activity seems to be good for cardiovascular health, with no apparent upper limit to the benefits.


Ramakrishnan R, Doherty A, Smith-Byrne K, Rahimi K, Bennett D, Woodward M, et al. (2021) Accelerometer measured physical activity and the incidence of cardiovascular disease: Evidence from the UK Biobank cohort study. PLoS Med 18(1): e1003487. doi:10.1371/journal.pmed.1003487 Accelerometer measured physical activity and the incidence of cardiovascular disease: Evidence from the UK Biobank cohort study

Why was this study done?

There is an inverse association between self-reported physical activity (PA) and occurrence of cardiovascular disease (CVD). However, there is uncertainty about the strength of this association as self-reported questionnaires are subject to differential measurement error.

Accelerometers are small lightweight motion sensors that are typically worn on the wrist. They more reliably measure PA status and thus could improve understanding of associations with CVD.

What did the researchers do and find?

We used data from 90,211 UK Biobank participants without prior CVD who agreed to wear an accelerometer to measure their PA status over 7 days.

Higher levels of PA were associated with lower risk for CVD that was similar across total, moderate- and vigorous-intensity PA.

What do these findings mean?

Our findings suggest that individuals who engage in higher levels of PA have lower risk for CVD throughout the range of PA measured.

The lowest risk for CVD in the UK Biobank cohort is seen at the highest level of PA, whether total, moderate-intensity, or vigorous-intensity.

Background - Higher levels of physical activity (PA) are associated with a lower risk of cardiovascular disease (CVD). However, uncertainty exists on whether the inverse relationship between PA and incidence of CVD is greater at the highest levels of PA. Past studies have mostly relied on self-reported evidence from questionnaire-based PA, which is crude and cannot capture all PA undertaken. We investigated the association between accelerometer-measured moderate, vigorous, and total PA and incident CVD.

Methods and findings - We obtained accelerometer-measured moderate-intensity and vigorous-intensity physical activities and total volume of PA, over a 7-day period in 2013–2015, for 90,211 participants without prior or concurrent CVD in the UK Biobank cohort.

Participants in the lowest category of total PA smoked more, had higher body mass index and C-reactive protein, and were diagnosed with hypertension. PA was associated with 3,617 incident CVD cases during 440,004 person-years of follow-up (median (interquartile range [IQR]): 5.2 (1.2) years) using Cox regression models.

We found a linear dose–response relationship for PA, whether measured as moderate-intensity, vigorous-intensity, or as total volume, with risk of incident of CVD. Hazard ratios (HRs) and 95% confidence intervals for increasing quarters of the PA distribution relative to the lowest fourth were for moderate-intensity PA: 0.71 (0.65, 0.77), 0.59 (0.54, 0.65), and 0.46 (0.41, 0.51); for vigorous-intensity PA: 0.70 (0.64, 0.77), 0.54 (0.49,0.59), and 0.41 (0.37,0.46); and for total volume of PA: 0.73 (0.67, 0.79), 0.63 (0.57, 0.69), and 0.47 (0.43, 0.52).

We took account of potential confounders but unmeasured confounding remains a possibility, and while removal of early deaths did not affect the estimated HRs, we cannot completely dismiss the likelihood that reverse causality has contributed to the findings. Another possible limitation of this work is the quantification of PA intensity-levels based on methods validated in relatively small studies.

Conclusions - In this study, we found no evidence of a threshold for the inverse association between objectively measured moderate, vigorous, and total PA with CVD. Our findings suggest that PA is not only associated with lower risk for of CVD, but the greatest benefit is seen for those who are active at the highest level.

 

[Michael Scally MD]

[OA] Centenarians-A Model to Study the Molecular Basis of Lifespan and Healthspan

People are living longer, not, as was previously the case, due to reduced child mortality, but because we are postponing the ill-health of old age. The global population aged 60 years or over numbered 962 million in 2017, more than twice as large as in 1980 when there were 382 million older persons worldwide.

The number of older persons is expected to double again by 2050, when it is projected to reach nearly 2.1 billion; the number of persons aged 80 years or over is projected to increase more than threefold between 2017 and 2050, rising from 137 million to 425 million.

Ageing is a component of life, which derives from the breakdown of the self-organization system and the reduced ability to adapt to the environment. As we age, harmful changes accumulate in the molecules, cells and tissues responsible for the decline of normal physiological functions. This inexorably leads to a reduced ability of the individual to maintain adequate homeostasis, resulting in a greater susceptibility to different types of stressors. Hence, ageing processes are defined as those that amplify the vulnerability of individuals, as they age, to the factors that ultimately lead to death.

This extraordinary increase in older people emphasizes the importance of studies on ageing and longevity and the need for a prompt dissemination of knowledge on ageing and longevity with the aim to satisfactorily diminish the medical, economic and social problems associated with advancing years, problems caused by the continuous increase in the number of older people at risk of frailty and age-related diseases.

In fact, the increase in the duration of life (lifespan) does not coincide with the increase in the duration of health (healthspan), that is the period of life free from serious chronic diseases and disabilities.

Therefore, improving the quality of life of older people must be a priority. This makes studies of the processes involved in ageing and longevity of great importance.

In particular, understanding why some individuals have escaped from neonatal mortality, infectious diseases in the pre-antibiotic era and the fatal outcomes of age-related diseases, thus living 100+ years, might allow the factors involved in the attainment of healthy ageing. For scientists, centenarians are, in fact, the paradigmatic example of healthy ageing.

Caruso C, Puca AA. Special Issue "Centenarians-A Model to Study the Molecular Basis of Lifespan and Healthspan". Int J Mol Sci. 2021 Feb 19;22(4):2044. doi: 10.3390/ijms22042044. PMID: 33669501. https://www.mdpi.com/1422-0067/22/4/2044/htm