Can Your Pancreas Get Old?

“I’m very pleased to be here. Let’s face it, at my age I’m very pleased to be anywhere.” George Burns

Ageing is a part of life. Presumably, all organ systems of the human body are afflicted by the ageing process. Liver volume decreases by 20–40% with age as the result of a decline in liver perfusion. Individuals aged 65 years or older show an approximately 35% decrease in blood volume of the liver compared with the age group below 40 years. Furthermore, the decrease not only pertains to the total liver volume but also to the mass of functional liver cells. The volume of the kidneys also decreases with age. The number of glomeruli decreases at a rate of 6752 per year after the age of 18 years. The average kidney mass decreases from >400 g during the 3rd and 4th decade to <300 g by the 9th decade. The resorptive capacity of the intestine also decreases with age, both in man and mice, due to reduced enzymatic capacity of the brush border, a reduction in the mucosal surface area in healthy elderly and reduction in villus height. It is therefore reasonable to suggest that the pancreas also may change its morphology and function with increasing age. However studies on age-related changes affecting pancreatic volume and structure have reported contradictory findings, and most importantly not all changes are pathological.

What Happens To The Pancreas Structurally As We Age?

Autopsy studies have reported that with advancing age, fibrosis and lipomatosis occur in the pancreas, ductal epithelial changes are present, and the pancreatic duct may be more dilated than in younger individuals. The weight of the pancreas decreases continuously from the age of 40 until advanced age. Pancreatic volume reaches a maximal mean value of 78.85 cm3 in the third decade of life. The volume of the pancreas then decreases significantly with increasing age and it shrinks at the age of 70–80 years to only 57.35 cm3.

In an autopsy study by Detlefsen et al. fibrotic changes were significantly more common in individuals over 60 years of age. Persons whose ages ranged from 20 to 59 only rarely exhibited pancreatic fibrosis. The probability of pancreatic fibrosis in groups <60 years old and ≥60 years old was 10.3% and 62.0%, respectively. Normal pancreatic tissues from 60-to 86-year-old subjects frequently showed focal lobular fibrosis.

Stamm observed in an autopsy study a clear progression of lipomatosis with the age of the patients. The average age of the patients without any detectable fat replacement was 21 years. The average age of the group with fat replacement of less than a quarter of the pancreas was 61.4 years. The fatty infiltration of the pancreas is different from that of the liver. In fatty liver disease, the fat accumulates in the hepatocytes. Pancreatic steatosis is histologically characterized by an increased number of adipocytes.

Healthy women had a higher pancreatic fat fraction than their male counterparts of the same age. Yang et al. found that pancreatic fat percentage remained unchanged in healthy women with normal BMI between 20 and 40 years of age but increased significantly by 70.0% and 25.9% between 41 and 50 years of age and 51 and 70 years of age, respectively. These results suggest that the increase in pancreatic fat begins in the fifth decade of life. The pancreatic fat fraction of healthy women aged 41–70 years was still higher than that of women aged 20–40 years, which suggested that aging was an independent risk factor for pancreatic fat deposition in healthy women and that both aging and menopause were responsible for the increased pancreatic fat fraction of healthy women older than 40 years. While in healthy men the increase in the fat fraction in the pancreas began in the 6th decade of life, in healthy women, fat infiltration in the pancreas occurred about 10 years earlier than in healthy men.

The pathophysiological mechanisms of pancreatic lipomatosis and fibrosis are not well understood. There are some data suggesting that age-related atherosclerosis and decreased perfusion of the pancreas is the cause of fibrosis. What is important to remember is that these changes are not necessarily pathologic. This clearly should be distinguished from NAFPD (non-alcoholic fatty pancreas disease). Risk factors for the development of NAFPD are obesity, increasing age, male gender, dyslipidemia, alcohol abuse, arterial hypertension, and hyperferritinemia.

The photomicrographs below depict normal pancreas (a) and the aged pancreas (b), with focal fat and thick bands of fibrosis (thin arrows).

But Is Any Of This Stuff Bad For You?

It is widely accepted that the morphology of the pancreas determines its function. Hence exploring age-related morphological and pathological changes in the pancreas can help understand the pathogenesis of pancreatic diseases in the elderly while enhancing a healthy lifespan.

What may be far more important pathologically in pancreatic senescence is genetic damage, DNA methylation, endoplasmic reticulum (ER) stress, mitochondrial dysfunction, weakening of the immune system, and inflammation. Inflammation may in fact be the most important negative factor. The majority of the pancreatic tissue develops a low-level chronic inflammatory state with age. The inflammatory microenvironment of the aging pancreas may be the major cause of the age-dependent deterioration in endocrine function and the progressive loss of functional β-cells, as we covered in a prior Sweetbreads newsletter.

Endocrine Dysfunction

During aging, β-cells undergo several metabolic changes. Proliferation and regeneration are impaired and the secretory capacity is reduced. Therefore, aging-related degeneration of β-cells contribute to impaired glucose homeostasis and T2D. Multiple studies have demonstrated that the decreased proliferative potential of aging β-cells was associated with decreased cell cycle activators and increased cell cycle inhibitors. Secreting insulin to maintain glucose homeostasis is a major indicator of β-cell function. The effects of senility on both basal insulin secretion (fasting insulin levels) and glucose-stimulated insulin secretion (GSIS) have been controversial. There are three main theories about the insulin-secreting ability of senescent β-cells: (1) unlike young β-cells, senescent β-cells show an age-dependent decline in GSIS and basal insulin secretion. This theory was thought to be related to the reduction of islet proliferation and regeneration during senescence. (2) Basal insulin secretion does not change significantly or decrease but GSIS increases in aging β-cells, suggesting that insulin secretion in hypoglycemia and hyperglycemia is controlled by distinct mechanisms and can be uncoupled.

Chronic exposure of pancreatic β-cells to high glucose and free fatty acid concentrations results in increased intracellular triglyceride accumulation and β-cell dysfunction. Fat deposition in the pancreas may affect predominantly the islets of Langerhans, but alternatively and in addition also acinar cells. Metabolic and morphologic consequences include decreased insulin secretion, insulin resistance, apoptosis of pancreatic exocrine cells, and replacement by adipocytes and connective tissue. This results in a positive feedback process or vicious cycle which, as part of the metabolic syndrome, can lead to various other clinical consequences in addition to the acceleration of type 2 diabetes mellitus and obesity. The associated clinical consequences include a tendency for acute pancreatitis to become more severe, the development of exocrine insufficiency, and also an increase in the risk of developing ductal adenocarcinoma with a potentially less favorable prognosis.

Exocrine Dysfunction

In most studies, the exocrine function of the pancreas was found to be impaired with increasing age. Duodenal aspirates from older individuals contained significantly reduced concentrations of pancreatic enzymes compared to aspirates from younger subjects: enzyme output following secretin stimulation was 40% reduced in older subjects as compared to younger individuals.

In a recent study, fecal elastase-1 was measured in over 1000 individuals with gastrointestinal symptoms but without known pancreatic disease. Of those aged over 70, 10% had low fecal elastase-1 (<200 μg) compatible with exocrine pancreatic insufficiency, and 5% had fecal elastase-1 < 100 μg. In comparison, in patients with ordinary chronic pancreatitis, EPI is diagnosed in 50% after a disease duration of 5 years and almost 100% after 10 years. Taken together, these findings imply that pancreatic enzyme secretion and function are impaired in healthy older individuals without underlying gastrointestinal diseases due to age-related changes. This decrease in pancreatic secretion is also seen in older rats.

Pancreatic Carcinogenesis

Probably the most important finding as far as pancreatic cancer (PDAC) etiology goes is the finding of pancreatic intraepithelial neoplasia (PanIN). PanIN was first proposed in 1994. This lesion may originate in any part of the pancreatic duct system, including the main pancreatic duct. PanIN lesions are classified into PanIN-1A, -1B, -2, and -3 types based on the degree of architectural and cytological atypia observed on histopathological examination. The normal ductal lining showing nonmucinous, cuboidal to low-columnar epithelial cells is replaced initially by tall columnar mucinous epithelium with minimal cytological atypia (PanIN-1A), which progresses to the PanIN-1B type in which minimally atypical tall columnar mucinous epithelium shows the development of micropapillae or papillae. PanIN-2 lesions are characterized by increasing cytological atypia, and PanIN-3 lesions show more complex and severe architectural and cytological atypia.

PanIN is one of the three main precursors of PDAC, the other two being mucinous cystic neoplasm and IPMN. PanIN lesions are rare in patients aged <40 years and occur more commonly in those aged >40 years. Multiple lines of evidence suggest that PanIN lesions are associated with fibrosis, and the prominent fibrosis in the pancreatic body and tail might contribute to the higher incidence of PanIN identified in these locations, which may explain the reportedly high incidence of PDAC in the pancreatic body and tail in elderly patients.

In addition, PanIN lesions were subject to age-related changes in telomerase function. Telomeres are tandem arrays of TTAGGG sequence repeats at chromosomal ends in eukaryotes and play a key role in preventing chromosomal instability. As people age, telomerase activity either slows or stops and a transient period of telomere shortening and dysfunction triggers carcinogenesis via induction of chromosomal instability. Telomeres in the normal duct epithelium were observed to become shorter with age, and telomeres in the duct epithelium in patients with PanIN lesions or cancers were shorter than those in age-matched controls.

While the stepwise accumulation of oncogenic mutations is required for the development of PDAC, prior work on the aging tumor microenvironment has identified that advancing age alters the function of nonmalignant cells in ways that promote cancer initiation, pointing to a role for aged microenvironments (TME) in the initiation and progression of many cancers. Age-related changes in nonmalignant cells that ultimately comprise the TME have been identified as drivers of cancer growth and progression.

PDAC tumors contain a small epithelial component that is surrounded by a larger fibroblast-rich stroma. These cancer-associated fibroblasts (CAF) dominate the tumor mass and are known mediators of tumor progression and therapy resistance through mechanisms including release of protumor signaling factors into the microenvironment.

Elegant research by Zabransky et al. (just published this year) found that aged pancreatic fibroblasts (from donors > 55 years of age) enhanced proliferation, migration, and invasion of PDAC cells through many growth factors. One such aging-induced pancreatic fibroblast-derived factor is GDF-15, which was highly secreted by aged pancreatic fibroblasts compared with young pancreatic fibroblasts. This novel age-driven microenvironmental source of GDF-15 was responsible for increasing the tumorigenic properties of PDAC cells in their study.

Can Anything Actually Be Done To Slow Aging?

Two drugs have been proposed to slow pancreatic aging. Resveratrol and metformin can ameliorate β-cell senescence and improve metabolic balance in animal models. In diabetic individuals, metformin is suggested to improve glucose tolerance and insulin sensitivity by reducing telomere shortening, preventing inflammation and oxidation and shifting the gut macrobiotia composition. See here and here. However, exercise and an antioxidant-rich diet may go even further.

The Future?

No article in 2024 could be considered complete without a discussion of AI. There is an evolving concept of "abdominal age". Biological "abdominal age" represents the state of the body of an individual and it is the true underlying cause of age-related diseases. It is in contrast with chronological age --commonly referred to as "age"-- the time since the individual’s birth.

Can a machine learning model be built to help predict a patient's "abdominal age"? It turns out that the answer is yes! Le Goallec et al. reported in 2022 on a study of 36,784 pancreas MRIs. They were able to accurately assess a patient's "abdominal biological age" based on this model and correlate it with various genetic and physical biomarkers of aging, including genes identified on GWAS that are associated with aging, body impedance, blood pressure, and pulse wave analysis.

The three environmental variable categories most associated with accelerated abdominal aging were smoking, sun exposure and alcohol intake. Specifically, 37.5% of smoking variables were associated with accelerated abdominal aging, with the three largest associations being with pack years adult smoking as proportion of lifespan exposed to smoking. Interesting!

Conclusion

Age-related changes in the pancreas result in non-pathologic fibrosis, atrophy and fatty infiltration, as well as the pathologic entities of exocrine pancreas insufficiency, diabetes, and pancreatic cancer. Much work still remains to help separate the two states and possibly help shed more light on how tractable (or intractable) the biology of aging is. The fountain of youth obviously has yet to be discovered, despite claims to the contrary by Ponce de León.

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